果蝇(Drosophila)Wingless和Hedgehog信号传导途径的调控
|
摘要
通过运用Vestigial-gal4，UAS-FLP系统把重组酶专一性地传递到翅中的新遗传筛选体系来进行遗传筛选，由于在F1即进行筛选，故称F1遗传筛选。根据翅的表型筛选出突变体以后，对这些突变体果蝇的生殖系克隆胚胎的表皮形态进行分析，从而进一步确认该突变的性质。从该F1遗传筛选中分离出了很多已知基因的突变体等位基因，其中包括了那些与Wingless(Wg)信号传导途径和Hedgehog(Hh)信号传导途径相关的突变体等位基因。同时，也分离出了一些未知基因的突变体等位基因。本文对其中与Wg信号传导途径和Hh信号传导途径相关的三类突变体等位基因(每一类都有三到四个突变体等位基因)进行了深入的研究。并通过综合分析翅的形态，生殖系克隆胚胎的表皮形态，以及缺失作图，直接测序和搜索基因组数据库，鉴定出了三个基因，这三个基因分别对应于该三类突变体等位基因。同时，对这三个基因在果蝇Wg信号传导途径和Hh信号传导途径中的作用也进行了研究。
1、分离到的第一类突变体等位基因的有B158，B140和B173。试验表明具该类突变体等位基因的果蝇呈现类似于wg突变的翅表型，生殖系克隆胚胎也呈现表皮混合的典型wg突变表型。这些突变或是无义突变(B158和B140)或是破坏原初转录本剪接的突变(B173)。sll基因编码一个高尔基体PAPS转运子。Kyte-Doolittle疏水性分析结果表明，与其它转运子相似，Sll蛋白是一个疏水性很强的蛋白(尤其在它的C端)。
通过对sll生殖系克隆胚胎进行的抗Engrailed(En)抗体染色和wg反义探针的原位杂交结果表明，与野生型果蝇的胚胎相比较，En蛋白和wg转录物条带出现了明显的缺失。胚胎分析结果表明sll基因的突变会导致wg转录和engrailed基因的表达受到抑制。进一步结合运用FLP-FRT系统和minute~-，用缺损Myc蛋白的表达来标记纯合的sll突变基因克隆，用minute~-来相对的扩大含sll突变基因的克隆，对翅成虫盘所作的克隆分析表明，在含sll突变基因的克隆中，细胞外的Wg蛋白分布明显减少，这种细胞外的Wg蛋白减少表明在翅成虫盘中Wg信号传导受到了明显抑制。
2、分离到的第二类突变体等位基因的有15-108，A164，B104和L5。具该类突变体等位基因的果蝇呈现出与Wg和Hh信号传导途径相关的翅和表皮形态。这一组突变体等位基因编码一种木糖转移酶-Oxt，这种转移酶能够将UDP-木糖
中的木糖转移到核。0蛋白的丝氨酸（Serine）残基上。该组的三个突变体等位基
因的突变都是无义突变，它们都破坏了。Xt基因的编码区。通过把。Xt基因加上
GFP标记，发现该基因主要在细胞质中表达。将OX亡蛋白的保守结构域和哺乳动
物的同源基因的保守结构域进行比较，发现这些保守区域在所比较的脊椎动物和
无脊椎动物中都十分保守。
通过对 oxt生殖系克隆胚胎进行的抗 En抗体染色和 wg反义探针a杂交结
果表明，与野生型果蝇的胚胎相比，En蛋白和wg转录物条带都出现了明显的缺
失。胚胎分析结果表明则t基因的突变会导致wg的转录和engrailed基因的表
达受抑。进一步结合运用FLP－FRT系统，用缺损GFP蛋白的表达来标记纯合的
OXt突变基因克隆，针对眼睛成虫盘的克隆分析结果表明，在OXt突变克隆中，
Hh下游的以蛋白的表达区域完全消失。Ci蛋白的表达区域完全消失表明Hh信
号传导受到了明显抑制。
3、分离到的第三类突变体等位基因包括F66，F15亿8，F126和F107。具该
类突变体等位基因的果蝇呈现出类似于把突变的表型，生殖系克隆胚胎也呈现
表皮混合表型。这组的突变体等位基因编码一个Wg信号传导途径组成成分
干gg由 其特点是在 N端含有一个核定位信号mLS），而在 C端则含有一个 PHO
结构域（一种C4HC3锌指结构）。测序结果表明其中H个突变体等位基因F66，
F15－108和F126均是无义突变。无义突变会导致不完整的蛋白产物的产生。F107
有一个突变位点在PHD域内，该突变把PHD结构域（C4HC3）中的最后一个半脱
氨酸（Cysteine）突变成络氨酸（Tyrosine）。
Wg信号传导途径是果蝇和脊椎动物中的一个关键性的信号传导途径。已经
鉴定出来许多参与 Wg／Wnt信号传导通路的基因。Wg下游的 Wg信号传导是由
核 TCFIEFI 通过 Amadillo（Ann）／P－catenin介导的。PygoPusoygo）是 W洲nt
信号传导通路的成员。通过本研究的细胞定位实验发现PygO专一性的表达在细
胞核中，这与其含有一个核定位信号（NLS）是一致的。运用反义探针做原位杂
交观察到了pygo基因在果蝇胚胎中的表达特性。结果表明，虽然pygo普遍表
达于整个胚胎中，并且在果蝇胚胎发生全过程都有，但n000在前囊胚层
…亿七lastoderm冲的表达水平相对较高，这说明胚胎发生过程中来自母方的贡献
较高。在幼虫组织（包括翅成虫盘，眼成虫盘和腿成虫盘）的发育过程中，PygO
的表达水平总的来说比较低。然而，比较翅成虫盘，眼成虫盘和腿成虫盘的PygO
表达水平，则在翅成虫盘和腿成虫盘PygO的表达水平相对较高。
6
本研究加深了对Wg、信号传导
By using a vestigial-ga14 to deliver the tissue specific flipase to the wing, a F1 genetic screen was performed. A number of mutant alleles of known or unknown genes were isolated from this Fl screen. This study focused on three groups of mutant alleles from mutant alleles of unknown genes. All these three groups of alleles related to either Wingless (Wg) signaling pathway or Hedgehog (Hh) signaling pathway (each group composed of 3-4 mutant alleles). By analyzing the wing phenotype, cuticle phenotype of germline clone embryo, deficiency kit mapping, direct sequencing and searching the genome sequence database, three genes: sll, oxt and pygo were identified (each gene corresponding to one group of mutant alleles).
1) The first group of the mutant alleles included B158, B140 and B173. These alleles showed wg-like phenotype (notch et al.), the germline clone embryo showed cuticle fusion phenotype. This group of mutant alleles turned out to be a gene encoding a Golgi adenosine 3'-phosphate 5'-phosphsulfate transporter (adenosine PAPS transporter). Kyte-Doolittle hydrophilicity plots showed that Sll is a very hydrophobic protein, especially in C terminus. The nature of the mutant alleles is either nonsense mutation or the mutation which disrupted the splicing of the primary transcripts.
Anti-En antibody staining and in situ hybridization on sll Germline clone (GLC) embryo using wg antisense probe showed defective En protein bands and defective wg transcripts bands. Furthermore, the wing imaginal disc clonal analysis showed that in the homozygous sll mutant clones, the extracellular Wg was dramatically reduced. The reduction of extracellular Wg indicated that the Wg signaling in the wing imaginal disc was disrupted. The reason leaded to this phenomenon is that sll encodes a PAPS transporter, so the disruption of the sll gene would generate the unsulfated Heparan Sulfate Proteoglycan (HSPG), which most likely would lose normal function.
2) The second group of mutant alleles included 15-108. A164, B104 and L5. These alleles showed wing and cuticle phenotypes related to both Wg and Hh signaling pathways (notch and vein defect et al.). This group of mutant alleles turned out to be a gene encoding a xylosyltransferase, which is an enzyme transfers the xylose from UDP-xylose to the serine of the protein core. The nature of all the three mutant alleles of this group is nonsense mutation disrupting the coding region of oxt gene. By tagging the oxt gene with a GFP tag, it was found that this gene mainly expressed in the cytosol. Comparison of conserved domains (Core-2/ I-Branching and Wsc domain) of Oxt with mammalian homologues showed that both of domains are conserved throughout the invertebrate and vertebrate.
Anti-En antibody staining and in situ hybridization on oxt GLC embryo using wg antisense probe showed defective En protein and defective wg transcripts bands. The embryonic analysis results indicated that the disruption of oxt gene would lead to the disruption of wg transcription and the expression of engrailed gene, as the wg
transcription is dependant on the Engrailed. Clonal analysis in this study on the eye imaginal disc showed that in the oxt mutant clones, the Ci expression was completely deleted. On the Hh signal receiving cells, the function of HSPG in HhN movement might be that it competes with Ptc for binding of HhN, following the releasing from the Disp, HhN binds to the HSPG to prevent the HhN from being captured by the Ptc, hence facilitate it's transfer to the more distantly located cells. Also, HSPG might also be required for secreting cells: as a co-factor for secreting cells to displace the HhN from the Disp.
3) The 3rd group of mutant alleles included F66, F15-28, F126 and F107. These alleles showed wing and cuticle phenotypes related to Wg signaling pathway. This group of mutant alleles turned out to be a new component of Wg singaling pathway. The sequence result showed that the nature of pygo mutant alleles F66, F15-108 and F126 were nonsense mutation, which probably led to tru
1、分离到的第一类突变体等位基因的有B158，B140和B173。试验表明具该类突变体等位基因的果蝇呈现类似于wg突变的翅表型，生殖系克隆胚胎也呈现表皮混合的典型wg突变表型。这些突变或是无义突变(B158和B140)或是破坏原初转录本剪接的突变(B173)。sll基因编码一个高尔基体PAPS转运子。Kyte-Doolittle疏水性分析结果表明，与其它转运子相似，Sll蛋白是一个疏水性很强的蛋白(尤其在它的C端)。
通过对sll生殖系克隆胚胎进行的抗Engrailed(En)抗体染色和wg反义探针的原位杂交结果表明，与野生型果蝇的胚胎相比较，En蛋白和wg转录物条带出现了明显的缺失。胚胎分析结果表明sll基因的突变会导致wg转录和engrailed基因的表达受到抑制。进一步结合运用FLP-FRT系统和minute~-，用缺损Myc蛋白的表达来标记纯合的sll突变基因克隆，用minute~-来相对的扩大含sll突变基因的克隆，对翅成虫盘所作的克隆分析表明，在含sll突变基因的克隆中，细胞外的Wg蛋白分布明显减少，这种细胞外的Wg蛋白减少表明在翅成虫盘中Wg信号传导受到了明显抑制。
2、分离到的第二类突变体等位基因的有15-108，A164，B104和L5。具该类突变体等位基因的果蝇呈现出与Wg和Hh信号传导途径相关的翅和表皮形态。这一组突变体等位基因编码一种木糖转移酶-Oxt，这种转移酶能够将UDP-木糖
中的木糖转移到核。0蛋白的丝氨酸（Serine）残基上。该组的三个突变体等位基
因的突变都是无义突变，它们都破坏了。Xt基因的编码区。通过把。Xt基因加上
GFP标记，发现该基因主要在细胞质中表达。将OX亡蛋白的保守结构域和哺乳动
物的同源基因的保守结构域进行比较，发现这些保守区域在所比较的脊椎动物和
无脊椎动物中都十分保守。
通过对 oxt生殖系克隆胚胎进行的抗 En抗体染色和 wg反义探针a杂交结
果表明，与野生型果蝇的胚胎相比，En蛋白和wg转录物条带都出现了明显的缺
失。胚胎分析结果表明则t基因的突变会导致wg的转录和engrailed基因的表
达受抑。进一步结合运用FLP－FRT系统，用缺损GFP蛋白的表达来标记纯合的
OXt突变基因克隆，针对眼睛成虫盘的克隆分析结果表明，在OXt突变克隆中，
Hh下游的以蛋白的表达区域完全消失。Ci蛋白的表达区域完全消失表明Hh信
号传导受到了明显抑制。
3、分离到的第三类突变体等位基因包括F66，F15亿8，F126和F107。具该
类突变体等位基因的果蝇呈现出类似于把突变的表型，生殖系克隆胚胎也呈现
表皮混合表型。这组的突变体等位基因编码一个Wg信号传导途径组成成分
干gg由 其特点是在 N端含有一个核定位信号mLS），而在 C端则含有一个 PHO
结构域（一种C4HC3锌指结构）。测序结果表明其中H个突变体等位基因F66，
F15－108和F126均是无义突变。无义突变会导致不完整的蛋白产物的产生。F107
有一个突变位点在PHD域内，该突变把PHD结构域（C4HC3）中的最后一个半脱
氨酸（Cysteine）突变成络氨酸（Tyrosine）。
Wg信号传导途径是果蝇和脊椎动物中的一个关键性的信号传导途径。已经
鉴定出来许多参与 Wg／Wnt信号传导通路的基因。Wg下游的 Wg信号传导是由
核 TCFIEFI 通过 Amadillo（Ann）／P－catenin介导的。PygoPusoygo）是 W洲nt
信号传导通路的成员。通过本研究的细胞定位实验发现PygO专一性的表达在细
胞核中，这与其含有一个核定位信号（NLS）是一致的。运用反义探针做原位杂
交观察到了pygo基因在果蝇胚胎中的表达特性。结果表明，虽然pygo普遍表
达于整个胚胎中，并且在果蝇胚胎发生全过程都有，但n000在前囊胚层
…亿七lastoderm冲的表达水平相对较高，这说明胚胎发生过程中来自母方的贡献
较高。在幼虫组织（包括翅成虫盘，眼成虫盘和腿成虫盘）的发育过程中，PygO
的表达水平总的来说比较低。然而，比较翅成虫盘，眼成虫盘和腿成虫盘的PygO
表达水平，则在翅成虫盘和腿成虫盘PygO的表达水平相对较高。
6
本研究加深了对Wg、信号传导
By using a vestigial-ga14 to deliver the tissue specific flipase to the wing, a F1 genetic screen was performed. A number of mutant alleles of known or unknown genes were isolated from this Fl screen. This study focused on three groups of mutant alleles from mutant alleles of unknown genes. All these three groups of alleles related to either Wingless (Wg) signaling pathway or Hedgehog (Hh) signaling pathway (each group composed of 3-4 mutant alleles). By analyzing the wing phenotype, cuticle phenotype of germline clone embryo, deficiency kit mapping, direct sequencing and searching the genome sequence database, three genes: sll, oxt and pygo were identified (each gene corresponding to one group of mutant alleles).
1) The first group of the mutant alleles included B158, B140 and B173. These alleles showed wg-like phenotype (notch et al.), the germline clone embryo showed cuticle fusion phenotype. This group of mutant alleles turned out to be a gene encoding a Golgi adenosine 3'-phosphate 5'-phosphsulfate transporter (adenosine PAPS transporter). Kyte-Doolittle hydrophilicity plots showed that Sll is a very hydrophobic protein, especially in C terminus. The nature of the mutant alleles is either nonsense mutation or the mutation which disrupted the splicing of the primary transcripts.
Anti-En antibody staining and in situ hybridization on sll Germline clone (GLC) embryo using wg antisense probe showed defective En protein bands and defective wg transcripts bands. Furthermore, the wing imaginal disc clonal analysis showed that in the homozygous sll mutant clones, the extracellular Wg was dramatically reduced. The reduction of extracellular Wg indicated that the Wg signaling in the wing imaginal disc was disrupted. The reason leaded to this phenomenon is that sll encodes a PAPS transporter, so the disruption of the sll gene would generate the unsulfated Heparan Sulfate Proteoglycan (HSPG), which most likely would lose normal function.
2) The second group of mutant alleles included 15-108. A164, B104 and L5. These alleles showed wing and cuticle phenotypes related to both Wg and Hh signaling pathways (notch and vein defect et al.). This group of mutant alleles turned out to be a gene encoding a xylosyltransferase, which is an enzyme transfers the xylose from UDP-xylose to the serine of the protein core. The nature of all the three mutant alleles of this group is nonsense mutation disrupting the coding region of oxt gene. By tagging the oxt gene with a GFP tag, it was found that this gene mainly expressed in the cytosol. Comparison of conserved domains (Core-2/ I-Branching and Wsc domain) of Oxt with mammalian homologues showed that both of domains are conserved throughout the invertebrate and vertebrate.
Anti-En antibody staining and in situ hybridization on oxt GLC embryo using wg antisense probe showed defective En protein and defective wg transcripts bands. The embryonic analysis results indicated that the disruption of oxt gene would lead to the disruption of wg transcription and the expression of engrailed gene, as the wg
transcription is dependant on the Engrailed. Clonal analysis in this study on the eye imaginal disc showed that in the oxt mutant clones, the Ci expression was completely deleted. On the Hh signal receiving cells, the function of HSPG in HhN movement might be that it competes with Ptc for binding of HhN, following the releasing from the Disp, HhN binds to the HSPG to prevent the HhN from being captured by the Ptc, hence facilitate it's transfer to the more distantly located cells. Also, HSPG might also be required for secreting cells: as a co-factor for secreting cells to displace the HhN from the Disp.
3) The 3rd group of mutant alleles included F66, F15-28, F126 and F107. These alleles showed wing and cuticle phenotypes related to Wg signaling pathway. This group of mutant alleles turned out to be a new component of Wg singaling pathway. The sequence result showed that the nature of pygo mutant alleles F66, F15-108 and F126 were nonsense mutation, which probably led to tru
引文
Ahn J, Ludecke H J, Lindow S et al. 1995. Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nat Genet 11:137-143
Alcedo J and Noll M 1997. Hedgehog and its patched-smoothened receptor complex: a novel signalling mechanism at the cell surface. Biol Chem 378: 583-590
Amiri A and Stein D 2002. Dorsoventral patterning: a direct route from ovary to embryo. Curr Biol. 12: 532
Anderson KV 1998. Pinning down positional information: dorsal-ventral polarity in the Drosophila embryo Cell 95:439-442
Ashburner, Michael 1989. Drosophila, a Laboratory Manuel, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York.
Baeg GH, Lin X, Khare N et al. 2001. Heparan Sulfate Proteoglycans are critical for the organization of the extracellular distribution of Wingless. Development 128:87-94
Bale AE 2002 Hedgehog signaling and human disease. Annu Rev Genomics Hum Genet 3:47-65
Basler K and Struhl G 1994. Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature 368:208-214
Behrens J, von Kries JP, Kuhl M et al. 1996. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382:638-642
Beiman M, Shilo BZ and Volk T 1996. Heartless, a Drosophila FGF receptor homolog, is essential for cell migration and establishment of several mesodermal lineages. Genes Dev 10:2993-3002
Bejsovec A, Martinez Arias A 1991. Roles of wingless in patterning the larval epidermis of Drosophila. Development 113:471-485
Belenkaya TY, Han C, Standley HJ et al. 2002. pygopus Encodes a nuclear protein essential for wingless/Wnt signaling. Development 129:4089-4101
Bellaiche Y, The I, Perrimon N 1998. Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion. Nature 394:85-88
Bernards A and Hariharan IK 2001 Of flies and men--studying human disease in Drosophila. Curr Opin Genet Dev. 11: 274-278
Bernfield M, Gtte M, Park PW et al. 1999. Function of cell surface heparan sulfate proteoglycans Annu Rew Biochem. 68:729-777
Bhanot P, Brink M, Samos CH et al. 1996. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 382:225-230
Bhanot P, Fisl M, Jemison JA et al. 1999. Frizzled and DFrizzled-2 function as redundant receptors for Wingless during Drosophila embryonic development. Development 126:4175-4186
Bier E and Reiter LT 2002 Using Drosophila melanogaster to uncover human disease gene function and potential drug target proteins. Expert Opin Ther Targets. 6:387-399
Binari RC, Staveley BE, Johnson WA et al. 1997. Genetic evidence that heparin-like glycosaminoglycans are involved in Wingless signaling. Development 124:2623-2632
Bradley RS and Brown AM 1990. The proto-oncogene int-1 encodes a secreted protein associated with the extracellular matrix. EMBO J 9:1569-1575
Brand AH and Perrimon N 1993. Target gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118:401-415
Briscoe J and Ericson J 1999 The specification of neuronal identity by graded Sonic Hedgehog signalling. Semin Cell Dev Biol. 10:353-362
Briscoe J, Sussel L, Serup P et al. 1999. Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling. Nature 398:622-627
Brown NH, Kafatos FC 1988. Functional cDNA libraries from Drosophila embryos. J Mol Biol 203: 425-437
Burke R, Nellen D, Bellotto M et al. 1999. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell 99:803-815
Cadigan KM, and Nusse R 1997. Wnt signaling: a common theme in animal development. Genes Dev 11: 3286-3305
Cadigan KM, Fish MP, Rulifson EJ et al. 1998. Wingless repression of Drosophila frizzled 2 expression shapes the Wingless morphogen gradient in the wing. Cell 93:767-777
Cadigan KM, Nusse R 1997. Wnt signaling: a common theme in animal development. Genes Dev 11: 3286-3305
Campbell G, Weaver T, Tomlinson A 1993. Axis specification in the developing Drosophila appendage: The role of wingless, decapentaplegtic and the homeobox gene aristaless. Cell 74:1113-1123
Chamoun Z, Mann RK, Nellen D et al. 2001. Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science 293:2080-2084
Chen Y, Struhl G 1996. Dual roles for patched in sequestering and transducing hedgehog. Cell 87: 553-563
Chen Y, Struhl G 1998. in vivo evidence that Patched and Smoothened constitute distinct binding and transducing components of a Hedgehog receptor complex. Development 125: 4943-4948
Chou TB and Perrimon N 1992. Use of a yeast site-specific recombinase to produce female germline chimeras in Drosophila. Genetics 131:643-653
Chou TB, Noll E, Perrimon N 1993. Autosomal P[ovo~(D1)] dominant femalesterile insertions in Drosophila and their use in generating germ-line chimeras. Development 119: 1359-1369
Cohen B, Simcox AA, Cohen SM 1993. Allocation of the thoracic imaginal primordia in the Drosophila embryo. Development 117:597-608
David AP, Romain RV, Jeremy ET et al. 1998. Heparan Sulfate Oligosaccharides Require 6-O-Sulfation for Promotion of Basic Fibroblast Growth Factor Mitogenic Activity J Biol Chem 273: 22936-22942
Demerec M (editor) 1950. Biology of Drosophila, Hafner Publishing Company, New York.
Duffy JB 2002. GAL4 system in Drosophila: a fly geneticist's Swiss army knife. Genesis. 34:1-15
Duffy JB, Harrison DA, Perrimon N 1998. Identifying loci required for follicular patterning using directed mosaics. Development 125:2263-2271
Entchev EV, Schwabedissen A., Gonzalez-Gaitan M 2000 Gradient Formation of the TGF-β Homolog Dpp. Cell 103:981-991
Esko JD 1991. Genetic analysis of proteoglycan structure, function and metabolism. Curr Opin Cell Biol 3:805-816
Q'7
Fantl WJ, Johnson DE and Williams LT 1993. Signalling by receptor tryrosine kinases. Annu Rev Biochem 62:453-481
Filmus J 2001 Glypicans in growth control and cancer. Glycobiology. 11:19-23
Freeman M 2000. Feedback control of intercellular signaling in development. Nature 408:313-319
Freifeider D 1993. Essentials of Molecular Biology, Jones and Bartlett Publishers, Boston, Mass.
Fuse N, Hirose S, Hayashi S 1996. Determination of wing cell fate by the escargot and snail genes in Drosophila. Development 122:1059-1067
Fyrberg E (editor) 1994. Drosophila melanogaster, Practice and Uses in Cell and Molecular Biology? Vol 44 Journal, Methods in Cell Biology, Academic Press, San Diego, Calf.
Gallagher JT, Turnbull JE 1992. Heparan sulphate in the binding and activation of basic fibroblast growth factor. Glycobiology. 2:523-528
Gonick L 1991. The Cartoon Guide to Genetics, Harper Perennial, New York.
Gonzalez F, Swales L, Bejsovec A et al. 1991. Secreton and movement of the wingless protein in the epidermis of the Drosophila embryo. Mech Der 35:43-54
Goodrich LV and Scott MP 1998. Hedgehog and patched in neural development and disease. Neuron 21: 1243-1257
Gotting C, Kuhn J, Brinkmann T et al. 2002. Xylosyltransferase activity in seminal plasma of infertile men, Clin Chim Acta 317:199-202
Gotting C, Sollberg S, Kuhn J et al. 1999. Serum xylosyltransferase: a new biochemical marker of the sclerotic process in systemic sclerosis. J Invest Dermatol. 112:919-924
Greco V, Hannus M, Eaton S 2001. Argosomes: a potential vehicle for the spread of morphogens through epithelia. Cell 106:633-645
Griffiths AJF, Miller JH, Suzuki DT et al. 1999. Introduction to Genetic Analysis 7th edition W.H. Freeman and Company, Salt Lake City, Utah.
Hacker U, Lin X, Perrimon N 1997. The Drosophila sugarless gene modulates Wingless signaling and encodes an enzyme involved in polysaccharide. Development 124:3565-3573
Haerry TE, Heslip TR, Marsh JL et al. 1997. Defects in glucuronate biosynthesis disrupt Wingless signaling in Drosophila. Development 124:3055-3064
Hempel J, Perozich J, Romovacek H et al. 1994. UDP-glucose dehydrogenase from bovine liver: Primary structure and relationship to other dehydrogenases. Protein Sci 3:1074-1080
Ingham PW 2000. Hedgehog signalling: How cholesterol modulates the signal Curr boil 10:180-183
Ingle T, Bellaiche Y, Perrimon N 1999. "Evidence that Heparan Sulfate Proteoglycans are involved in the movement of Hedgehog molecules through filed of cells." Molecular Cell 4:633-639
Jackson SM, Nakato H, Sugiura M et al. 1997. dally, a Drosophila glypican, controls cellular responses to the TGF-beta-related morphogen, Dpp. Development 124:4113-4120
Kamimura K, Fujise M, Villa F et al. 2001 Drosophila Heparan Sulfate 6-O-Sulfo transferase (dHS6ST) Gene. STRUCTURE, EXPRESSION, AND FUNCTION IN THE FORMATION OF THE TRACHEAL SYSTEM J Biol Chem 276:17014-17021
Khare N and Baumgartner S 2000 Dally-like protein, a new Drosophila glypican with expression overlapping with wingless. Mech Dev. 99:199-202
Kiger JA Jr, O'Shea C 2001. Genetic evidence for a protein kinase A/cubitus interruptus complex that facilitates processing of cubitus interruptus in Drosophila. Genetics. 158:1157-1166
Kitagawa H, Shimakawa H, Sugahara K 1999. "The tumor suppressor EXT-like gene EXTL-2 encodes an alphal,4-N-acetyihexosaminyltransferase that transfers N-acetyigalactosamine and N-acetylglucosamine to the common glycosaminoglycan-protein liknkage region. The key enzyme for the chain initiation of heparan sulfate." J Biol Chem 274:13933-13937
Kjellan L and Lindahl U 1991. Proteoglycans:structures and interactions. Annu Rev Biochem 60:443-475
Klmbt C, Glazer L, Shilo BZ 1992. breathless, a Drosophila FGF receptor homoiog, is essential for migration of tracheal and specific midline glial cells. Genes Dev. 6:1668-1678.
Korinek V, Barker N, Morin PJ et al. 1997. Constitutive transcriptional activation by aβ-catenin-Tcf complex in APC-/- colon carcinoma. Science 275:1784-1787
Kramps T, Peter O, Brunner E et al. 2002. Wnt/Wingless signaling Requires BCL9/Legless-Mediated Recruitment of Pygopus to the Nuclear beta-Catenin-TCF Complex. Cell 109:47-60
Kuhn J, Gotting C, Schnolzer M et al. 2001. First isolation of human UDP-D-xylose: proteoglycan core protein beta-D-xyiosyltransferase secreted from cultured JAR choriocarcinoma cells. J Biol Chem 276: 4940-4947
Lander AD and and Selleck SB 2000 The elusive functions of proteoglycans: in vivo veritas. J Cell Biol 148:227-232
Lasko P 2002 Diabetic flies? Using Drosophila melanogaster to understand the causes of monogenic and genetically complex diseases. Clin Genet. 62:358-367
Lawrence P A 1992. The Making of a Fly, Blackwell Scientific Publications, London.
Lawrence P, Casal J, Struhl G 1999. The hedgehog morphogen and gradients of cell affinity in the abdomen of Drosophila. Development 126:2441-2449
Lawrence PA and Struhl, G 1996. Morphogens, compartments and pattern: Lessons from Drosophila. Cell 85:951-961
Lee JD, Treisman JE 2001. The role of Wingless signaling in establishing the anteroposterior and dorsoventral axes of the eye disc. Development 128:1519-1529
Lefers MA and Holmgren R 2002. Ci proteolysis: regulation by a constellation of phosphorylation sites. Curt Biol 12:422-423
Lefers MA, Wang QT, Holmgren RA 2001. Genetic dissection of the Drosophila Cubitus interruptus signaling complex. Dev Biol. 236:411-420
Lehmann R, Tautz D 1994. in situ hybridization. In Drosophila melanogaster: Practical Uses in Cell and Molecular Biology: 575-598. San Diego, CA: Academic Press, Inc.
Li H, Deyrup A, Mensch JR Jr et al. 1995. The isolation and characterization of cDNA encoding the mouse bifunctional ATP sulfurylase-adenosine 5'-phosphosulfate kinase. J Biol Chem 270:29453-29459
Lin X and Perrimon N 1999a. Dally cooperates with Drosophila Frizzled 2 to transduce Wingless signalling. Nature 400:281-284
Lin X, Buff EM, Perrimon N et al. 1999b. Heparan sulfate proteoglycans are essential for FGF receptor signaling during Drosophila embryonic development. Development 126:3715-3723
Lindahl U, Kusche-Gullberg M, Kjellen L 1998. Regulated diversity of heparan sulfate. J Biol Chem
273: 24979-24982
Lindsley D 1992. The Genome of Drosophila melanogaster, Academic Press Inc, San Diego, California.
Lodish H, Berk A, Zipursky SL et al. 1999. Molecular Cell Biology. 4th edition. New York: W H Freeman & Co.
Mandon EC, Milla ME, Kmpner E et al. 1994 Purification of the Golgi adenosine 3'-phosphate 5'-phosphosulfate transporter, a homodimer within the membrane Proc Natl Acad Sci USA 91: 10707-10711
Marigo V, Davey RA, Zuo Y et al. 1996. Biochemical evidence that Patched is the Hedgehog receptor. Nature 384:176-179
McCormick C, Leduc Y, Martindale D et al. 1998. The putative tumour suppressor EXT1 alters the expression of cell- surface heparan sulfate. Nat Genet 19:158-161
McMahon AP 2000 More surprises in the Hedgehog signaling pathway. Cell: 100:185-188.
Neumann CJ and Cohen SM 1997. Long-range action of Wingless organizes the dorsal-ventral axis of the Drosophila wing. Development 124:871-880
Nusse R and Varmus HE 1992. Wnt genes. Cell 69:1073-1087
Nüsselein-Volhard C and Wieschaus E 1980 Mutations affectiong segment number and polarity in Drosophila. Nature 287:795-801
Nüsselein-Volhard C, Wieschaus E, Kluding H 1984. Mutations affecting the pattern of the larval cuticle in Drosophila melanogaster. Ⅱ. Zytotic loci on the third chromosome. Wilhelm Roux's Arch 193: 283-295
Nybakken K and Perrimon N 2002 Heparan sulfate proteoglycan modulation of developmental signaling in Drosophila. Biochim Biophys Acta. 1573:280-291
Pai LM, Orsulic S, Bejsovec A et al. 1997. Negative regulation of Armadillo, a Wingless effector in Drosophila. Development 124:2255-2266
Parker DS, Jemison J, Cadigan KM 2002. Pygopus, a nuclear PHD-finger protein required for Wingless signaling in Drosophila. Development 129:2565-2576
Parr BA and McMahon AP 1994. Wnt genes and vertebrate development. Curr Opin Genet Dev 4: 523-528
Peifer M. and Polakis P 2000 Wnt signaling in oncogenesis and embryogenesis-a look outside the nucleus. Science 287:1606-1609
Pellegrini L, Burke DF, von Delft F, Mulloy B et al. 2000 Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin. Nature 407:1029-1034
Penton A, Selleck SB, Hoffmann FM 1997. Regulation of cell cycle synchronization by decapentaplegic during Drosophila eye development. Science 275:203-206
Pepinsky RB, Zeng C, Wen D et al. 1998. Identification of a palmitic acid-modified form of human Sonic hedgehog. J Biol Chem 273:14037-14045
Perrimon N, and Bernfield M 2000. Specificities of heparan sulphate proteoglycans in developmental processes. Nature 404:725-728
Pfeiffer S, Alexandre C, Calleja M et al. 2000. The progeny of wingless-expressing cells deliver the signal at a distance in Drosophila embryos. Current Biol 10:321-324
Pfeiffer S, Ricardo S, Manneville JB et aL 2002. Producing cells retain and recycle wingless in Drosophila embryos. Curr Biol 12:957-962
Pilia G, Hughes-Benzie RM, MacKenzie A et al. 1996. Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat Genet 12:241-247
Porter J, Young K, Beachy P 1996. Cholesterol modification of Hedgehog signaling proteins in animal development. Science 274:255-259
Pye DA, Vires RR, Hyde P et al. 2000. Regulation of FGF-I mitogenic activity by heparan sulfate oligosaccharides is dependent on specific structural features: differential requirements for the modulation of FGF-1 and FGF-2. Glycobiology 10:1183-1192
Raftery LA and Sutherland DJ 1999 TGF-b Family Signal Transduction in Drosophila Development: From Mad to Smads Developmental Biology 210:251-268
Reichsman F, Smith L, Cumberledge S 1996. Glycosaminoglycans can modulate extracellular localization of the Wingless protein and promote signal transduction. J Cell Biol 135:819-827
Rosenberg RD, Shworak NW, Liu J et al. 1997a. Heparan sulfate proteoglycans of the cardiovascular system. Specific structures emerge but how is synthesis regulated? J Clin Invest 99: 2062-2070
Rosenberg RD, Shworak NW, Liu J et al. 1997b. Heparan sulfate proteoglycans of the cardiovascular system. Specific structures emerge but how is synthesis regulated? J Clin Invest 100:67-75
Rothe P, Sazbo K, Bailey A et al. 1998. Systematic gain-of-function genetics in Drosophila. Development 126: 1049-1057
Rubin JB, Choi Y, Segal RA 2002. Cerebellar proteoglycans regulate sonic hedgehog responses during development. Development 129:2223-2232
Sambrook J, Fritsch EF and Maniatis T 2001. Molecular cloning: A laboratory manual. Third edition. Cold Spring Harbor Laboratory Press, New York
Sanson B, Alexandre C, Fascetti N et al. 1999. Engrailed and hedgehog make the range of Wingless asymmetric in Drosophila embryos. Cell 98:207-216
Sanson B. 2001. Generating patterns from fields of cells. Examples from Drosophila segmentation. EMBO Rep 2(12): 1083-1088
Schlessinger J, Lax I, and Lemmon. M 1995. Regulation of growth factor activation by proteoglycans: what is the role of the low affinity receptors? Cell 83:357-360
Schlessinger J, Plotnikov AN, Ibrahimi OA et al. 2000 Crystal Structure of a Ternary FGF-FGFR-Heparin Complex Reveals a Dual Role for Heparin in FGFR Binding and Dimerization Mol. Cell 6:743-750
Selleck SB 2000. Proteoglycans and pattern formation: sugar biochemistry meets developmental genetics. Trends Genet 16:206-212
Selva EM, Hong K, Baeg GH et al. 2001 Dual role of the fringe connection gene in both heparan sulphate and fringe-dependent signalling events. Nat cell boil 3:809-815
Sen J, Goltz JS, Konsolaki M et al. 2000. Windbeutel is required for function and correct subcellular localization of the Drosophila patterning protein Pipe. Development. 127:5541-5550
Sen J, Goltz JS, Stevens L et al. 1998. "Spatially restricted expression of pipe in the Drosophila egg chamber defines embryonic dorsal-ventral polarity." Cell 95:471-481
Sergeev P, Streit A, Heller A et al. 2001. The Drosophila dorsoventral determinant PIPE contains ten copies of a variable domain homologous to mammalian heparan sulfate 2-sulfotransferase. Dev Dyn. 2001 220:122-32.
Siegfried E and Perrimon N 1994. Drosophila wingless: a paradigm for the function and mechanism of Wnt signaling. Bioessays 16:395-404
Spradling AC, Stern DM, Kisss I et aL 1995. Gene disruptions using P transposable elements: an integral component of the Drosophila genome project. Proc Natl Acad Sci USA 92:10824-10830
Stegman MA, Vallance JE, Eiangovan G et al.2000 Identification of a tetrameric hedgehog signaling complex. J Biol Chem. 275:21809-21812
Stickens D, Clines G, Burbee D et al. 1996. The EXT2 multiple exostoses gene defines a family of putative tumor suppressor genes. Nat Genet 14:25-32
Stone DM, Hynes M, Armanini M et al. 1996. The tumor-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 384:129-134
Strigini M and Cohen S 1997. A hedgehog activity gradient contributes to ap axial patterning of the Drosophila wing. Development 124:4697-4705
Strigini M and Cohen SM 1999. Formation of morphogen gradients in the Drosophila wing. Semin Cell Dev Biol 10: 335-344.
Strigini M and Cohen SM 2000. Wingless gradient formation in the Drosophila wing. Curr Biol 10: 293-300
Struhl G and Basler K 1993. Organizing activity of wingless protein in Drosophila. Cell 72:527-540
Struhl G, Barbash D, Lawrence P 1997. Hedgehog acts by distinct gradient and signal relay mechanisms to organize cell-type and cell polarity in the Drosophila abdomen. Development 124:2155-2165
Sturtevant MA and Bier E 1995. Analysis of the genetic hierarchy guiding wing vein development in Drosophila. Development 121:785-801
Sulston IA and Anderson KV 1998. Altered patterns of gene expression in Tribolium segmentation mutants. Dev Goner 23:56-64
Sutherland D, Samakovlis C and Krasnow M 1996. Branchless encodes a Drosophila FGF homolog that controls tracheal cell migration and the pattern of branching. Cell 87:1091-1101
Tamai K, Semenov M, Kato Y et al. 2000. LDL-receptor-related proteins in Wnt signal transduction. Nature 407:530-535
Teleman AA and Cohen SM 2000 Dpp Gradient Formation in the Drosophila Wing Imaginal Disc Cell 103: 971- 980
Thompson BF, Townsley R, Rosin-Arbesfeld R et al. 2002. A new nuclear component of the Wnt signalling pathway. Nature Cell Biology 4:367-373
Toyoda H, Kinoshita-Toyoda A, Fox B et al. 2000. Structural Analysis of Glycosaminoglycans in Animals Bearing Mutations in sugarless, sulfateless, and tout-velu. J Biol Chem 275:21856-21861
Tsuda M, Kamimura K, Nakato H et al. 1999. The cell-surface proteoglycan Dally regulates Wingless signaling in Drosophila. Nature 400:276-280
van de Wetering M, Cavallo R, Dooijes D et al. 1997. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCE Cell 88:789-799
van den Born J, Gunnarsson K, Bakker MA et al. 1995. Presence of N-unsubstituted glucosamine units
in native heparan sulfate revealed by a monoclonal antibody. J Biol Chem 270:31303-31309
van den Heuvel M and Ingham PW 1996. smoothened encodes a receptor-like serpentine protein required for Hedgehog signaling. Nature 382:547-551
van den Heuvel M, Nusse R, Johnston P et al. 1989. Distribution of the wingless gene product in Drosophila embryos: a protein involved in cell-cell communication. Cell 59:739-749
Vincent JP and Magee T 2002. Argosomes: membrane fragments on the run. Trends Cell Biol. 12:57-60
Walker A, Turnbull JE, Gallagher JT. 1994. Specific heparan sulfate saccharides mediate the activity of basic fibroblast growth factor. J Biol Chem. 269:931-935
Wang Y, Macke JP, Abella BS 1996. A large family of putative transmembrane receptors homologous to the product of the Drosophila tissue polarity gene frizzled. J Biol Chem 271:4468-4476
Wehrli M, Dougan ST, Caldwell K et al. 2000. arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 407:527-530
Williams S J, Senaratne RH, Mougous JD et al. 2002 5-Adenosinephosphosulfate Lies at a Metabolic Branch Point in Mycobacteria. J Biol Chem 277:32606-32615
Wilson IB 2002. Functional characterization of Drosophila melanogaster peptide O-xylosyltransferase, the key enzyme for proteoglycan chain initiation and member of the core 2/I N- acetylglucosaminyl -transferase family. J Biol Chem 277:21207-21212
Wodarz A and Nusse R 1998. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 14:59-88
Xu T and Rubin GM 1993. "Analysis of genetic mosaics in developing and adult Drosophila tissues." Development 117:1223-1237
Zecca M, Basler K, Struhl G 1996. Direct and long-range action of a wingless morphogen gradient. Cell 87:833-844
Alcedo J and Noll M 1997. Hedgehog and its patched-smoothened receptor complex: a novel signalling mechanism at the cell surface. Biol Chem 378: 583-590
Amiri A and Stein D 2002. Dorsoventral patterning: a direct route from ovary to embryo. Curr Biol. 12: 532
Anderson KV 1998. Pinning down positional information: dorsal-ventral polarity in the Drosophila embryo Cell 95:439-442
Ashburner, Michael 1989. Drosophila, a Laboratory Manuel, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York.
Baeg GH, Lin X, Khare N et al. 2001. Heparan Sulfate Proteoglycans are critical for the organization of the extracellular distribution of Wingless. Development 128:87-94
Bale AE 2002 Hedgehog signaling and human disease. Annu Rev Genomics Hum Genet 3:47-65
Basler K and Struhl G 1994. Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature 368:208-214
Behrens J, von Kries JP, Kuhl M et al. 1996. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382:638-642
Beiman M, Shilo BZ and Volk T 1996. Heartless, a Drosophila FGF receptor homolog, is essential for cell migration and establishment of several mesodermal lineages. Genes Dev 10:2993-3002
Bejsovec A, Martinez Arias A 1991. Roles of wingless in patterning the larval epidermis of Drosophila. Development 113:471-485
Belenkaya TY, Han C, Standley HJ et al. 2002. pygopus Encodes a nuclear protein essential for wingless/Wnt signaling. Development 129:4089-4101
Bellaiche Y, The I, Perrimon N 1998. Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion. Nature 394:85-88
Bernards A and Hariharan IK 2001 Of flies and men--studying human disease in Drosophila. Curr Opin Genet Dev. 11: 274-278
Bernfield M, Gtte M, Park PW et al. 1999. Function of cell surface heparan sulfate proteoglycans Annu Rew Biochem. 68:729-777
Bhanot P, Brink M, Samos CH et al. 1996. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 382:225-230
Bhanot P, Fisl M, Jemison JA et al. 1999. Frizzled and DFrizzled-2 function as redundant receptors for Wingless during Drosophila embryonic development. Development 126:4175-4186
Bier E and Reiter LT 2002 Using Drosophila melanogaster to uncover human disease gene function and potential drug target proteins. Expert Opin Ther Targets. 6:387-399
Binari RC, Staveley BE, Johnson WA et al. 1997. Genetic evidence that heparin-like glycosaminoglycans are involved in Wingless signaling. Development 124:2623-2632
Bradley RS and Brown AM 1990. The proto-oncogene int-1 encodes a secreted protein associated with the extracellular matrix. EMBO J 9:1569-1575
Brand AH and Perrimon N 1993. Target gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118:401-415
Briscoe J and Ericson J 1999 The specification of neuronal identity by graded Sonic Hedgehog signalling. Semin Cell Dev Biol. 10:353-362
Briscoe J, Sussel L, Serup P et al. 1999. Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling. Nature 398:622-627
Brown NH, Kafatos FC 1988. Functional cDNA libraries from Drosophila embryos. J Mol Biol 203: 425-437
Burke R, Nellen D, Bellotto M et al. 1999. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell 99:803-815
Cadigan KM, and Nusse R 1997. Wnt signaling: a common theme in animal development. Genes Dev 11: 3286-3305
Cadigan KM, Fish MP, Rulifson EJ et al. 1998. Wingless repression of Drosophila frizzled 2 expression shapes the Wingless morphogen gradient in the wing. Cell 93:767-777
Cadigan KM, Nusse R 1997. Wnt signaling: a common theme in animal development. Genes Dev 11: 3286-3305
Campbell G, Weaver T, Tomlinson A 1993. Axis specification in the developing Drosophila appendage: The role of wingless, decapentaplegtic and the homeobox gene aristaless. Cell 74:1113-1123
Chamoun Z, Mann RK, Nellen D et al. 2001. Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science 293:2080-2084
Chen Y, Struhl G 1996. Dual roles for patched in sequestering and transducing hedgehog. Cell 87: 553-563
Chen Y, Struhl G 1998. in vivo evidence that Patched and Smoothened constitute distinct binding and transducing components of a Hedgehog receptor complex. Development 125: 4943-4948
Chou TB and Perrimon N 1992. Use of a yeast site-specific recombinase to produce female germline chimeras in Drosophila. Genetics 131:643-653
Chou TB, Noll E, Perrimon N 1993. Autosomal P[ovo~(D1)] dominant femalesterile insertions in Drosophila and their use in generating germ-line chimeras. Development 119: 1359-1369
Cohen B, Simcox AA, Cohen SM 1993. Allocation of the thoracic imaginal primordia in the Drosophila embryo. Development 117:597-608
David AP, Romain RV, Jeremy ET et al. 1998. Heparan Sulfate Oligosaccharides Require 6-O-Sulfation for Promotion of Basic Fibroblast Growth Factor Mitogenic Activity J Biol Chem 273: 22936-22942
Demerec M (editor) 1950. Biology of Drosophila, Hafner Publishing Company, New York.
Duffy JB 2002. GAL4 system in Drosophila: a fly geneticist's Swiss army knife. Genesis. 34:1-15
Duffy JB, Harrison DA, Perrimon N 1998. Identifying loci required for follicular patterning using directed mosaics. Development 125:2263-2271
Entchev EV, Schwabedissen A., Gonzalez-Gaitan M 2000 Gradient Formation of the TGF-β Homolog Dpp. Cell 103:981-991
Esko JD 1991. Genetic analysis of proteoglycan structure, function and metabolism. Curr Opin Cell Biol 3:805-816
Q'7
Fantl WJ, Johnson DE and Williams LT 1993. Signalling by receptor tryrosine kinases. Annu Rev Biochem 62:453-481
Filmus J 2001 Glypicans in growth control and cancer. Glycobiology. 11:19-23
Freeman M 2000. Feedback control of intercellular signaling in development. Nature 408:313-319
Freifeider D 1993. Essentials of Molecular Biology, Jones and Bartlett Publishers, Boston, Mass.
Fuse N, Hirose S, Hayashi S 1996. Determination of wing cell fate by the escargot and snail genes in Drosophila. Development 122:1059-1067
Fyrberg E (editor) 1994. Drosophila melanogaster, Practice and Uses in Cell and Molecular Biology? Vol 44 Journal, Methods in Cell Biology, Academic Press, San Diego, Calf.
Gallagher JT, Turnbull JE 1992. Heparan sulphate in the binding and activation of basic fibroblast growth factor. Glycobiology. 2:523-528
Gonick L 1991. The Cartoon Guide to Genetics, Harper Perennial, New York.
Gonzalez F, Swales L, Bejsovec A et al. 1991. Secreton and movement of the wingless protein in the epidermis of the Drosophila embryo. Mech Der 35:43-54
Goodrich LV and Scott MP 1998. Hedgehog and patched in neural development and disease. Neuron 21: 1243-1257
Gotting C, Kuhn J, Brinkmann T et al. 2002. Xylosyltransferase activity in seminal plasma of infertile men, Clin Chim Acta 317:199-202
Gotting C, Sollberg S, Kuhn J et al. 1999. Serum xylosyltransferase: a new biochemical marker of the sclerotic process in systemic sclerosis. J Invest Dermatol. 112:919-924
Greco V, Hannus M, Eaton S 2001. Argosomes: a potential vehicle for the spread of morphogens through epithelia. Cell 106:633-645
Griffiths AJF, Miller JH, Suzuki DT et al. 1999. Introduction to Genetic Analysis 7th edition W.H. Freeman and Company, Salt Lake City, Utah.
Hacker U, Lin X, Perrimon N 1997. The Drosophila sugarless gene modulates Wingless signaling and encodes an enzyme involved in polysaccharide. Development 124:3565-3573
Haerry TE, Heslip TR, Marsh JL et al. 1997. Defects in glucuronate biosynthesis disrupt Wingless signaling in Drosophila. Development 124:3055-3064
Hempel J, Perozich J, Romovacek H et al. 1994. UDP-glucose dehydrogenase from bovine liver: Primary structure and relationship to other dehydrogenases. Protein Sci 3:1074-1080
Ingham PW 2000. Hedgehog signalling: How cholesterol modulates the signal Curr boil 10:180-183
Ingle T, Bellaiche Y, Perrimon N 1999. "Evidence that Heparan Sulfate Proteoglycans are involved in the movement of Hedgehog molecules through filed of cells." Molecular Cell 4:633-639
Jackson SM, Nakato H, Sugiura M et al. 1997. dally, a Drosophila glypican, controls cellular responses to the TGF-beta-related morphogen, Dpp. Development 124:4113-4120
Kamimura K, Fujise M, Villa F et al. 2001 Drosophila Heparan Sulfate 6-O-Sulfo transferase (dHS6ST) Gene. STRUCTURE, EXPRESSION, AND FUNCTION IN THE FORMATION OF THE TRACHEAL SYSTEM J Biol Chem 276:17014-17021
Khare N and Baumgartner S 2000 Dally-like protein, a new Drosophila glypican with expression overlapping with wingless. Mech Dev. 99:199-202
Kiger JA Jr, O'Shea C 2001. Genetic evidence for a protein kinase A/cubitus interruptus complex that facilitates processing of cubitus interruptus in Drosophila. Genetics. 158:1157-1166
Kitagawa H, Shimakawa H, Sugahara K 1999. "The tumor suppressor EXT-like gene EXTL-2 encodes an alphal,4-N-acetyihexosaminyltransferase that transfers N-acetyigalactosamine and N-acetylglucosamine to the common glycosaminoglycan-protein liknkage region. The key enzyme for the chain initiation of heparan sulfate." J Biol Chem 274:13933-13937
Kjellan L and Lindahl U 1991. Proteoglycans:structures and interactions. Annu Rev Biochem 60:443-475
Klmbt C, Glazer L, Shilo BZ 1992. breathless, a Drosophila FGF receptor homoiog, is essential for migration of tracheal and specific midline glial cells. Genes Dev. 6:1668-1678.
Korinek V, Barker N, Morin PJ et al. 1997. Constitutive transcriptional activation by aβ-catenin-Tcf complex in APC-/- colon carcinoma. Science 275:1784-1787
Kramps T, Peter O, Brunner E et al. 2002. Wnt/Wingless signaling Requires BCL9/Legless-Mediated Recruitment of Pygopus to the Nuclear beta-Catenin-TCF Complex. Cell 109:47-60
Kuhn J, Gotting C, Schnolzer M et al. 2001. First isolation of human UDP-D-xylose: proteoglycan core protein beta-D-xyiosyltransferase secreted from cultured JAR choriocarcinoma cells. J Biol Chem 276: 4940-4947
Lander AD and and Selleck SB 2000 The elusive functions of proteoglycans: in vivo veritas. J Cell Biol 148:227-232
Lasko P 2002 Diabetic flies? Using Drosophila melanogaster to understand the causes of monogenic and genetically complex diseases. Clin Genet. 62:358-367
Lawrence P A 1992. The Making of a Fly, Blackwell Scientific Publications, London.
Lawrence P, Casal J, Struhl G 1999. The hedgehog morphogen and gradients of cell affinity in the abdomen of Drosophila. Development 126:2441-2449
Lawrence PA and Struhl, G 1996. Morphogens, compartments and pattern: Lessons from Drosophila. Cell 85:951-961
Lee JD, Treisman JE 2001. The role of Wingless signaling in establishing the anteroposterior and dorsoventral axes of the eye disc. Development 128:1519-1529
Lefers MA and Holmgren R 2002. Ci proteolysis: regulation by a constellation of phosphorylation sites. Curt Biol 12:422-423
Lefers MA, Wang QT, Holmgren RA 2001. Genetic dissection of the Drosophila Cubitus interruptus signaling complex. Dev Biol. 236:411-420
Lehmann R, Tautz D 1994. in situ hybridization. In Drosophila melanogaster: Practical Uses in Cell and Molecular Biology: 575-598. San Diego, CA: Academic Press, Inc.
Li H, Deyrup A, Mensch JR Jr et al. 1995. The isolation and characterization of cDNA encoding the mouse bifunctional ATP sulfurylase-adenosine 5'-phosphosulfate kinase. J Biol Chem 270:29453-29459
Lin X and Perrimon N 1999a. Dally cooperates with Drosophila Frizzled 2 to transduce Wingless signalling. Nature 400:281-284
Lin X, Buff EM, Perrimon N et al. 1999b. Heparan sulfate proteoglycans are essential for FGF receptor signaling during Drosophila embryonic development. Development 126:3715-3723
Lindahl U, Kusche-Gullberg M, Kjellen L 1998. Regulated diversity of heparan sulfate. J Biol Chem
273: 24979-24982
Lindsley D 1992. The Genome of Drosophila melanogaster, Academic Press Inc, San Diego, California.
Lodish H, Berk A, Zipursky SL et al. 1999. Molecular Cell Biology. 4th edition. New York: W H Freeman & Co.
Mandon EC, Milla ME, Kmpner E et al. 1994 Purification of the Golgi adenosine 3'-phosphate 5'-phosphosulfate transporter, a homodimer within the membrane Proc Natl Acad Sci USA 91: 10707-10711
Marigo V, Davey RA, Zuo Y et al. 1996. Biochemical evidence that Patched is the Hedgehog receptor. Nature 384:176-179
McCormick C, Leduc Y, Martindale D et al. 1998. The putative tumour suppressor EXT1 alters the expression of cell- surface heparan sulfate. Nat Genet 19:158-161
McMahon AP 2000 More surprises in the Hedgehog signaling pathway. Cell: 100:185-188.
Neumann CJ and Cohen SM 1997. Long-range action of Wingless organizes the dorsal-ventral axis of the Drosophila wing. Development 124:871-880
Nusse R and Varmus HE 1992. Wnt genes. Cell 69:1073-1087
Nüsselein-Volhard C and Wieschaus E 1980 Mutations affectiong segment number and polarity in Drosophila. Nature 287:795-801
Nüsselein-Volhard C, Wieschaus E, Kluding H 1984. Mutations affecting the pattern of the larval cuticle in Drosophila melanogaster. Ⅱ. Zytotic loci on the third chromosome. Wilhelm Roux's Arch 193: 283-295
Nybakken K and Perrimon N 2002 Heparan sulfate proteoglycan modulation of developmental signaling in Drosophila. Biochim Biophys Acta. 1573:280-291
Pai LM, Orsulic S, Bejsovec A et al. 1997. Negative regulation of Armadillo, a Wingless effector in Drosophila. Development 124:2255-2266
Parker DS, Jemison J, Cadigan KM 2002. Pygopus, a nuclear PHD-finger protein required for Wingless signaling in Drosophila. Development 129:2565-2576
Parr BA and McMahon AP 1994. Wnt genes and vertebrate development. Curr Opin Genet Dev 4: 523-528
Peifer M. and Polakis P 2000 Wnt signaling in oncogenesis and embryogenesis-a look outside the nucleus. Science 287:1606-1609
Pellegrini L, Burke DF, von Delft F, Mulloy B et al. 2000 Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin. Nature 407:1029-1034
Penton A, Selleck SB, Hoffmann FM 1997. Regulation of cell cycle synchronization by decapentaplegic during Drosophila eye development. Science 275:203-206
Pepinsky RB, Zeng C, Wen D et al. 1998. Identification of a palmitic acid-modified form of human Sonic hedgehog. J Biol Chem 273:14037-14045
Perrimon N, and Bernfield M 2000. Specificities of heparan sulphate proteoglycans in developmental processes. Nature 404:725-728
Pfeiffer S, Alexandre C, Calleja M et al. 2000. The progeny of wingless-expressing cells deliver the signal at a distance in Drosophila embryos. Current Biol 10:321-324
Pfeiffer S, Ricardo S, Manneville JB et aL 2002. Producing cells retain and recycle wingless in Drosophila embryos. Curr Biol 12:957-962
Pilia G, Hughes-Benzie RM, MacKenzie A et al. 1996. Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat Genet 12:241-247
Porter J, Young K, Beachy P 1996. Cholesterol modification of Hedgehog signaling proteins in animal development. Science 274:255-259
Pye DA, Vires RR, Hyde P et al. 2000. Regulation of FGF-I mitogenic activity by heparan sulfate oligosaccharides is dependent on specific structural features: differential requirements for the modulation of FGF-1 and FGF-2. Glycobiology 10:1183-1192
Raftery LA and Sutherland DJ 1999 TGF-b Family Signal Transduction in Drosophila Development: From Mad to Smads Developmental Biology 210:251-268
Reichsman F, Smith L, Cumberledge S 1996. Glycosaminoglycans can modulate extracellular localization of the Wingless protein and promote signal transduction. J Cell Biol 135:819-827
Rosenberg RD, Shworak NW, Liu J et al. 1997a. Heparan sulfate proteoglycans of the cardiovascular system. Specific structures emerge but how is synthesis regulated? J Clin Invest 99: 2062-2070
Rosenberg RD, Shworak NW, Liu J et al. 1997b. Heparan sulfate proteoglycans of the cardiovascular system. Specific structures emerge but how is synthesis regulated? J Clin Invest 100:67-75
Rothe P, Sazbo K, Bailey A et al. 1998. Systematic gain-of-function genetics in Drosophila. Development 126: 1049-1057
Rubin JB, Choi Y, Segal RA 2002. Cerebellar proteoglycans regulate sonic hedgehog responses during development. Development 129:2223-2232
Sambrook J, Fritsch EF and Maniatis T 2001. Molecular cloning: A laboratory manual. Third edition. Cold Spring Harbor Laboratory Press, New York
Sanson B, Alexandre C, Fascetti N et al. 1999. Engrailed and hedgehog make the range of Wingless asymmetric in Drosophila embryos. Cell 98:207-216
Sanson B. 2001. Generating patterns from fields of cells. Examples from Drosophila segmentation. EMBO Rep 2(12): 1083-1088
Schlessinger J, Lax I, and Lemmon. M 1995. Regulation of growth factor activation by proteoglycans: what is the role of the low affinity receptors? Cell 83:357-360
Schlessinger J, Plotnikov AN, Ibrahimi OA et al. 2000 Crystal Structure of a Ternary FGF-FGFR-Heparin Complex Reveals a Dual Role for Heparin in FGFR Binding and Dimerization Mol. Cell 6:743-750
Selleck SB 2000. Proteoglycans and pattern formation: sugar biochemistry meets developmental genetics. Trends Genet 16:206-212
Selva EM, Hong K, Baeg GH et al. 2001 Dual role of the fringe connection gene in both heparan sulphate and fringe-dependent signalling events. Nat cell boil 3:809-815
Sen J, Goltz JS, Konsolaki M et al. 2000. Windbeutel is required for function and correct subcellular localization of the Drosophila patterning protein Pipe. Development. 127:5541-5550
Sen J, Goltz JS, Stevens L et al. 1998. "Spatially restricted expression of pipe in the Drosophila egg chamber defines embryonic dorsal-ventral polarity." Cell 95:471-481
Sergeev P, Streit A, Heller A et al. 2001. The Drosophila dorsoventral determinant PIPE contains ten copies of a variable domain homologous to mammalian heparan sulfate 2-sulfotransferase. Dev Dyn. 2001 220:122-32.
Siegfried E and Perrimon N 1994. Drosophila wingless: a paradigm for the function and mechanism of Wnt signaling. Bioessays 16:395-404
Spradling AC, Stern DM, Kisss I et aL 1995. Gene disruptions using P transposable elements: an integral component of the Drosophila genome project. Proc Natl Acad Sci USA 92:10824-10830
Stegman MA, Vallance JE, Eiangovan G et al.2000 Identification of a tetrameric hedgehog signaling complex. J Biol Chem. 275:21809-21812
Stickens D, Clines G, Burbee D et al. 1996. The EXT2 multiple exostoses gene defines a family of putative tumor suppressor genes. Nat Genet 14:25-32
Stone DM, Hynes M, Armanini M et al. 1996. The tumor-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 384:129-134
Strigini M and Cohen S 1997. A hedgehog activity gradient contributes to ap axial patterning of the Drosophila wing. Development 124:4697-4705
Strigini M and Cohen SM 1999. Formation of morphogen gradients in the Drosophila wing. Semin Cell Dev Biol 10: 335-344.
Strigini M and Cohen SM 2000. Wingless gradient formation in the Drosophila wing. Curr Biol 10: 293-300
Struhl G and Basler K 1993. Organizing activity of wingless protein in Drosophila. Cell 72:527-540
Struhl G, Barbash D, Lawrence P 1997. Hedgehog acts by distinct gradient and signal relay mechanisms to organize cell-type and cell polarity in the Drosophila abdomen. Development 124:2155-2165
Sturtevant MA and Bier E 1995. Analysis of the genetic hierarchy guiding wing vein development in Drosophila. Development 121:785-801
Sulston IA and Anderson KV 1998. Altered patterns of gene expression in Tribolium segmentation mutants. Dev Goner 23:56-64
Sutherland D, Samakovlis C and Krasnow M 1996. Branchless encodes a Drosophila FGF homolog that controls tracheal cell migration and the pattern of branching. Cell 87:1091-1101
Tamai K, Semenov M, Kato Y et al. 2000. LDL-receptor-related proteins in Wnt signal transduction. Nature 407:530-535
Teleman AA and Cohen SM 2000 Dpp Gradient Formation in the Drosophila Wing Imaginal Disc Cell 103: 971- 980
Thompson BF, Townsley R, Rosin-Arbesfeld R et al. 2002. A new nuclear component of the Wnt signalling pathway. Nature Cell Biology 4:367-373
Toyoda H, Kinoshita-Toyoda A, Fox B et al. 2000. Structural Analysis of Glycosaminoglycans in Animals Bearing Mutations in sugarless, sulfateless, and tout-velu. J Biol Chem 275:21856-21861
Tsuda M, Kamimura K, Nakato H et al. 1999. The cell-surface proteoglycan Dally regulates Wingless signaling in Drosophila. Nature 400:276-280
van de Wetering M, Cavallo R, Dooijes D et al. 1997. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCE Cell 88:789-799
van den Born J, Gunnarsson K, Bakker MA et al. 1995. Presence of N-unsubstituted glucosamine units
in native heparan sulfate revealed by a monoclonal antibody. J Biol Chem 270:31303-31309
van den Heuvel M and Ingham PW 1996. smoothened encodes a receptor-like serpentine protein required for Hedgehog signaling. Nature 382:547-551
van den Heuvel M, Nusse R, Johnston P et al. 1989. Distribution of the wingless gene product in Drosophila embryos: a protein involved in cell-cell communication. Cell 59:739-749
Vincent JP and Magee T 2002. Argosomes: membrane fragments on the run. Trends Cell Biol. 12:57-60
Walker A, Turnbull JE, Gallagher JT. 1994. Specific heparan sulfate saccharides mediate the activity of basic fibroblast growth factor. J Biol Chem. 269:931-935
Wang Y, Macke JP, Abella BS 1996. A large family of putative transmembrane receptors homologous to the product of the Drosophila tissue polarity gene frizzled. J Biol Chem 271:4468-4476
Wehrli M, Dougan ST, Caldwell K et al. 2000. arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 407:527-530
Williams S J, Senaratne RH, Mougous JD et al. 2002 5-Adenosinephosphosulfate Lies at a Metabolic Branch Point in Mycobacteria. J Biol Chem 277:32606-32615
Wilson IB 2002. Functional characterization of Drosophila melanogaster peptide O-xylosyltransferase, the key enzyme for proteoglycan chain initiation and member of the core 2/I N- acetylglucosaminyl -transferase family. J Biol Chem 277:21207-21212
Wodarz A and Nusse R 1998. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 14:59-88
Xu T and Rubin GM 1993. "Analysis of genetic mosaics in developing and adult Drosophila tissues." Development 117:1223-1237
Zecca M, Basler K, Struhl G 1996. Direct and long-range action of a wingless morphogen gradient. Cell 87:833-844