Homeobox protein goosecoid

Homeobox protein goosecoid (GSC) is a homeobox protein that is encoded in humans by the GSC gene. Like other homeobox proteins, goosecoid functions as a transcription factor involved in morphogenesis. In Xenopus, GSC is thought to play a crucial role in the phenomenon of the Spemann-Mangold organizer.^[5] Through lineage tracing and timelapse microscopy, the effects of GSC on neighboring cell fates could be observed. In an experiment that injected cells with GSC and observed the effects of uninjected cells, GSC recruited neighboring uninjected cells in the dorsal blastopore lip of the Xenopus gastrula to form a twinned dorsal axis, suggesting that the goosecoid protein plays a role in the regulation and migration of cells during gastrulation.^[6][5]

GSC
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2DMU
Identifiers
Aliases	GSC, SAMS, goosecoid homeobox
External IDs	OMIM: 138890 MGI: 95841 HomoloGene: 7744 GeneCards: GSC
Gene location (Human) Chr. Chromosome 14 (human)^[1] Band 14q32.13 Start 94,768,223 bp^[1] End 94,770,113 bp^[1]
Gene location (Mouse) Chr. Chromosome 12 (mouse)^[2] Band 12 E|12 54.32 cM Start 104,437,468 bp^[2] End 104,439,589 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Achilles tendon subcutaneous adipose tissue gastrocnemius muscle right lobe of thyroid gland left lobe of thyroid gland tibial nerve skin of abdomen lymph node salivary gland minor salivary glands Top expressed in human mandible female urethra condyle male urethra left atrium hypoblast endoderm right atrium tongue thyroid gland More reference expression data BioGPS More reference expression data
Gene ontology Molecular function sequence-specific DNA binding DNA binding RNA polymerase II cis-regulatory region sequence-specific DNA binding DNA-binding transcription repressor activity, RNA polymerase II-specific DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component transcription regulator complex nucleus nuclear body Biological process embryonic skeletal system morphogenesis multicellular organism development neural crest cell fate specification negative regulation of Wnt signaling pathway forebrain development dorsal/ventral neural tube patterning anatomical structure morphogenesis signal transduction involved in regulation of gene expression ear development regulation of transcription, DNA-templated negative regulation of transcription by RNA polymerase II gastrulation muscle organ morphogenesis middle ear morphogenesis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 145258 14836 Ensembl ENSG00000133937 ENSMUSG00000021095 UniProt P56915 Q02591 RefSeq (mRNA) NM_173849 NM_010351 RefSeq (protein) NP_776248 NP_034481 Location (UCSC) Chr 14: 94.77 – 94.77 Mb Chr 12: 104.44 – 104.44 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

It is not clear how GSC conducts this organizational function. Errors in the formation of goosecoid protein in mice and humans have a range of consequences on the developing embryo typically in regions of neural crest cell derivatives, the hip and shoulder joints, and craniofacial development. Short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS) was thought to be a rare autosomal recessive developmental disorder, but through whole-exome sequencing, it was discovered that SAMS is the result of a mutation of the GSC gene.^[7] The data collected from the whole-exome sequencing, as well as the phenotypical presentation of SAMS, indicates that in mammals, the goosecoid protein is involved with the regulation and migration of neural crest cell fates and other mesodermal patterning, notably joints like the shoulders and hips.^[8]

Function

The GSC gene defines neural-crest cell-fate specification and contributes to dorsal-ventral patterning. Over activation in Xenopus promotes dorso-anterior migration and dorsalization of mesodermal tissue of the cells along with BMP-4.^[9] Conversely, loss-of-functions analysis indirectly prevented head formation in Xenopus ^[10] and head defects in zebrafish.^[11] Although, knock-out studies in mice showed that the GSC gene is not required for gastrulation, knocking out the gene results in there still being a reduction of the base of the cranium. A mutation in the GSC gene in Drosophila is lethal. ^[12]

GSC gene promotes the formation of Spemann’s Organizer. This organizer prevents BMP-4 from inducing the ectoderm in the future head region of the embryo to become epidermis; it instead allows the future head region to form neural folds, which will eventually turn into the brain and spinal cord. For normal anterior development to occur, Spemann’s organizer cannot express the Xwnt-8 or BMP-4 transcription factors. GSC directly represses the expression of Xwnt-8 while indirectly repressing BMP-4.^[13] The inhibition of Xwnt-8 and BMP-4 ensures that normal anterior development, promoted by Spemann’s organizer, can occur.

The expression of GSC occurs twice in development, first during gastrulation and second during organogenesis.^[14] GSC is found in high concentrations in the dorsal mesoderm and endoderm during gastrulation. The later expression of GSC is confined to the head region. In the frog Xenopus, cells that express GSC become the pharyngeal endoderm, the head's mesoderm, ventral skeletal tissue of the head, and the notocord.^[15]

Mutations

A mutation in the GSC gene causes short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS). SAMS was previously thought to be an autosomal-recessive disorder but studies with molecular karyotyping and whole-exome sequencing (WES) has shown otherwise.^[7]

Mutations in the Gsc gene can lead to specific phenotypes resulting from the second expression of the Gsc gene during organogenesis. Mice knock-out models of the gene express defects in the tongue, nasal cavity, nasal pits, inner ear, and external auditory meatus.^[16] Neonate mice born with this mutation die within 24 hours due to complication with breathing and sucking milk, resulting from the craniofacial abnormalities caused by the mutation. Mutations to the Gsc gene in humans can lead to a condition known as SAMS syndrome, characterized by short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities.^[7][17]

Role in cancer development

Due to its role as a transcription factor in cell migration during embryonic development, GSC has been looked into as a potential role-player in cancer development and metastasis, since embryonic development and cancer development share similar characteristics. GSC, along with other transcription factors like Twist, FOXC2, and Snail, induce epithelial to mesenchymal transitions by regulating the cell adhesion proteins E-cadherin, α-catenin and γ-catenin expression in epithelial cells.^[18] Studies have shown that in highly metastatic ovarian, lung, breast, and other cancer cells, GSC is highly expressed early in the progression of the tumor.^[19] Furthermore, high levels of GSC expression in cancer cells correlates with poor survival rates and thus can be used as a prognostic tool.^[20] High expression of GSC also correlates with the chemoresistance of the cancer. Therefore, GSC “primes cells for the expression of aggressive phenotypes^[19]” and “may be the most potential biomarker of drug response and poor prognosis.^[20]”

References

1. GRCh38: Ensembl release 89: ENSG00000133937 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000021095 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Xenopus Goosecoid". Interactive Fly, Drosophila.
6. Blum M, De Robertis EM, Kojis T, Heinzmann C, Klisak I, Geissert D, Sparkes RS (May 1994). "Molecular cloning of the human homeobox gene goosecoid (GSC) and mapping of the gene to human chromosome 14q32.1". Genomics. 21 (2): 388–93. doi:10.1006/geno.1994.1281. PMID 7916327.
7. Parry DA, Logan CV, Stegmann AP, Abdelhamed ZA, Calder A, Khan S, et al. (December 2013). "SAMS, a syndrome of short stature, auditory-canal atresia, mandibular hypoplasia, and skeletal abnormalities is a unique neurocristopathy caused by mutations in Goosecoid". American Journal of Human Genetics. 93 (6): 1135–42. doi:10.1016/j.ajhg.2013.10.027. PMC 3853132. PMID 24290375.
8. "Chicken Goosecoid". Interactive Fly, Drosophila.
9. Niehrs C, Keller R, Cho KW, De Robertis EM (1993). "The homeobox gene goosecoid controls cell migration in Xenopus embryos". Cell. 72 (4): 491–503. doi:10.1016/0092-8674(93)90069-3. PMID 8095000. S2CID 2147704.
10. Steinbeisser H, Fainsod A, Niehrs C, Sasai Y, De Robertis EM (November 1995). "The role of gsc and BMP-4 in dorsal-ventral patterning of the marginal zone in Xenopus: a loss-of-function study using antisense RNA". The EMBO Journal. 14 (21): 5230–43. doi:10.1002/j.1460-2075.1995.tb00208.x. PMC 394633. PMID 7489713.
11. Rivera-Pérez JA, Mallo M, Gendron-Maguire M, Gridley T, Behringer RR (September 1995). "Goosecoid is not an essential component of the mouse gastrula organizer but is required for craniofacial and rib development". Development. 121 (9): 3005–12. doi:10.1242/dev.121.9.3005. PMID 7555726.
12. Goriely A, Stella M, Coffinier C, Kessler D, Mailhos C, Dessain S, Desplan C (May 1996). "A functional homologue of goosecoid in Drosophila". Development. 122 (5): 1641–50. doi:10.1242/dev.122.5.1641. PMID 8625850.
13. Yao J, Kessler DS (August 2001). "Goosecoid promotes head organizer activity by direct repression of Xwnt8 in Spemann's organizer". Development. 128 (15): 2975–87. doi:10.1242/dev.128.15.2975. PMID 11532920.
14. Yamada G, Mansouri A, Torres M, Stuart ET, Blum M, Schultz M, De Robertis EM, Gruss P (September 1995). "Targeted mutation of the murine goosecoid gene results in craniofacial defects and neonatal death" (PDF). Development. 121 (9): 2917–22. doi:10.1242/dev.121.9.2917. PMID 7555718.
15. De Robertis E, Blum M, Niehrs C, Steinbeisser H (April 1992). "Mesoderm induction and origins of the embryonic axis: goosecoid and the organizer". Development. 116 (1): 167–171. doi:10.1242/dev.116.Supplement.167. PMID 1483385.
16. Yamada G, Ueno K, Nakamura S, Hanamure Y, Yasui K, Uemura M, Eizuru Y, Mansouri A, Blum M, Sugimura K (April 1997). "Nasal and pharyngeal abnormalities caused by the mouse goosecoid gene mutation". Biochemical and Biophysical Research Communications. 233 (1): 161–5. doi:10.1006/bbrc.1997.6315. PMID 9144415.
17. Lemire EG, Hildes-Ripstein GE, Reed MH, Chudley AE (January 1998). "SAMS: provisionally unique multiple congenital anomalies syndrome consisting of short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities". American Journal of Medical Genetics. 75 (3): 256–60. doi:10.1002/(sici)1096-8628(19980123)75:3<256::aid-ajmg5>3.0.co;2-o. PMID 9475592.
18. Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, Kutok JL, Hartwell K, Richardson AL, Weinberg RA (June 2007). "Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers". Proceedings of the National Academy of Sciences of the United States of America. 104 (24): 10069–74. Bibcode:2007PNAS..10410069M. doi:10.1073/pnas.0703900104. PMC 1891217. PMID 17537911.
19. Hartwell KA, Muir B, Reinhardt F, Carpenter AE, Sgroi DC, Weinberg RA (December 2006). "The Spemann organizer gene, Goosecoid, promotes tumor metastasis". Proceedings of the National Academy of Sciences of the United States of America. 103 (50): 18969–74. Bibcode:2006PNAS..10318969H. doi:10.1073/pnas.0608636103. PMC 1748161. PMID 17142318.
20. Kang KW, Lee MJ, Song JA, Jeong JY, Kim YK, Lee C, Kim TH, Kwak KB, Kim OJ, An HJ (July 2014). "Overexpression of goosecoid homeobox is associated with chemoresistance and poor prognosis in ovarian carcinoma". Oncology Reports. 32 (1): 189–98. doi:10.3892/or.2014.3203. PMID 24858567.

Further reading

• Schlade-Bartusiak K, Macintyre G, Zunich J, Cox DW (January 2008). "A child with deletion (14)(q24.3q32.13) and auditory neuropathy". American Journal of Medical Genetics Part A. 146A (1): 117–23. doi:10.1002/ajmg.a.32064. PMID 18074379. S2CID 13536206.
• Hartwell KA, Muir B, Reinhardt F, Carpenter AE, Sgroi DC, Weinberg RA (December 2006). "The Spemann organizer gene, Goosecoid, promotes tumor metastasis". Proceedings of the National Academy of Sciences of the United States of America. 103 (50): 18969–74. Bibcode:2006PNAS..10318969H. doi:10.1073/pnas.0608636103. PMC 1748161. PMID 17142318.
• Barrios-Rodiles M, Brown KR, Ozdamar B, Bose R, Liu Z, Donovan RS, Shinjo F, Liu Y, Dembowy J, Taylor IW, Luga V, Przulj N, Robinson M, Suzuki H, Hayashizaki Y, Jurisica I, Wrana JL (March 2005). "High-throughput mapping of a dynamic signaling network in mammalian cells". Science. 307 (5715): 1621–5. Bibcode:2005Sci...307.1621B. doi:10.1126/science.1105776. PMID 15761153. S2CID 39457788.
• Namciu SJ, Friedman RD, Marsden MD, Sarausad LM, Jasoni CL, Fournier RE (March 2004). "Sequence organization and matrix attachment regions of the human serine protease inhibitor gene cluster at 14q32.1". Mammalian Genome. 15 (3): 162–78. doi:10.1007/s00335-003-2311-y. PMID 15014966. S2CID 8594824.
• Foucher I, Montesinos ML, Volovitch M, Prochiantz A, Trembleau A (May 2003). "Joint regulation of the MAP1B promoter by HNF3beta/Foxa2 and Engrailed is the result of a highly conserved mechanism for direct interaction of homeoproteins and Fox transcription factors". Development. 130 (9): 1867–76. doi:10.1242/dev.00414. PMID 12642491.
• Danilov V, Blum M, Schweickert A, Campione M, Steinbeisser H (January 1998). "Negative autoregulation of the organizer-specific homeobox gene goosecoid". The Journal of Biological Chemistry. 273 (1): 627–35. doi:10.1074/jbc.273.1.627. PMID 9417125.

External links

• The Goosecoid Page at hhmi.ucla.edu