Homeobox protein goosecoid

Last updated
GSC
Protein GSC PDB 2dmu.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GSC , SAMS, goosecoid homeobox
External IDs OMIM: 138890; MGI: 95841; HomoloGene: 7744; GeneCards: GSC; OMA:GSC - orthologs
Orthologs
SpeciesHumanMouse
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

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]

Contents

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] ”

Related Research Articles

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The primitive node is the organizer for gastrulation in most amniote embryos. In birds, it is known as Hensen's node, and in amphibians, it is known as the Spemann-Mangold organizer. It is induced by the Nieuwkoop center in amphibians, or by the posterior marginal zone in amniotes including birds.

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Xbra is a homologue of Brachyury (T) gene for Xenopus. It is a transcription activator involved in vertebrate gastrulation which controls posterior mesoderm patterning and notochord differentiation by activating transcription of genes expressed throughout mesoderm. The effects of Xbra is concentration dependent where concentration gradient controls the development of specific types of mesoderm in Xenopus. Xbra results of the expression of the FGF transcription factor, synthesized by the ventral endoderm. So while ventral mesoderm is characterized by a high concentration of FGF and Xbra, the dorsal mesoderm is characterized by a reunion of two others transcription factors, Siamois and XnR, which activates the synthesis of Goosecoid Transcription Factor. Goosecoid enables the depletion of Xbra. In a nutshell, high concentrations of Xbra induce ventral mesoderm while low concentration stimulates the formation of a back.

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References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000133937 – Ensembl, May 2017
  2. 1 2 3 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. 1 2 "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. 1 2 3 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. 1 2 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. 1 2 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.

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