Homeobox protein goosecoid is a protein that in humans is encoded by the GSCgene. This gene encodes a member of the bicoid subfamily of the paired (PRD) homeobox family of proteins. The encoded protein acts as a transcription factor and may be autoregulatory. A similar protein in mice plays a role in craniofacial and rib cage development during embryogenesis.
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. Conversely, loss-of-functions analysis indirectly prevented head formation in Xenopus and head defects in zebrafish. Although, knock-out studies in mice showed that the GSC gene is not required for gastrulation but there is still reduction of the base of the cranium. A mutation in the GSC gene in Drosophila is lethal.
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. 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. 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 Xenopus, cells that express Gsc become the pharyngeal endoderm, the head mesoderm, ventral skeletal tissue of the head, and the notocord.
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.
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. 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.
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. 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. Furthermore, high levels of GSC expression in cancer cells correlates with poor survival rates and thus can be used as a prognostic tool. High expression of GSC also correlates with the chemoresistance of the cancer. Therefore, GSC “primes cells for the expression of aggressive phenotypes” and “may be the most potential biomarker of drug response and poor prognosis.”
^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. PMID7916327.
^Izpisúa-Belmonte JC, De Robertis EM, Storey KG, Stern CD (August 1993). "The homeobox gene goosecoid and the origin of organizer cells in the early chick blastoderm". Cell. 74 (4): 645–59. doi:10.1016/0092-8674(93)90512-o. PMID7916659.
^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. PMID7555726.
^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. PMID8625850.
^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". Development. 121 (9): 2917–22. PMID7555718.
^ abKang 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. PMID24858567.
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. PMID18074379.
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. doi:10.1126/science.1105776. PMID15761153.
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. PMID15014966.
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. PMID12642491.
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. PMID9417125.