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WikiJournal of Science/Grainyhead-like Genes in Regulating Development and Genetic Defects

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Article information

Abstract

The Grainyhead-like genes are a family of highly conserved transcription factors that are functionally and structurally homologous across a large number of vertebrate and invertebrate species. For an estimated 100 million years or more, this genetic family has been evolving alongside life to fine tune the regulation of epithelial barrier integrity during development, fine-tuning epithelial barrier establishment, maintenance and subsequent homeostasis. The three main orthologues, Grainyhead-like 1, 2 and 3, regulate numerous genetic pathways within different organisms and perform analogous roles between them, ranging from neural tube closure, wound healing, establishment of the craniofacial skeleton and repair of the epithelium. When Grainyhead-like genes are impaired, due to genetic mutations in embryogenesis, it will cause the organism to present with developmental defects that largely affect ectodermal (and sometimes also endodermal) tissues in which they are expressed. These subsequent congenital disorders, including cleft lip and exencephaly, vary greatly in their severity and impact on the quality of life for the affected individual. There is so much more to learn about the function of these genes and the more complex roles of Grainyhead-like genes are yet to be discovered.


 

 Comparison of WT (a, c) and Grhl3 KO (b, d) mice embryos at 18.5 days poss fertilization. It shows that Grhl3 KO mice have a shortened and flattened skull that is smaller in size overall, with a lack of vascularisation at the sutures. a-b are shown from a lateral view while c-d are shown from a dorsal view.[1]


Stephen Goldie, et al, CC BY

Grainyhead-like Gene Family

 

 Bright field microscopy of zebrafish, comparing control and morpholino (MO) mediated knockdown of grhl3 expression, showing that loss of grhl3 leads to defective craniofacial development. The red arrow highlights the defective jaw development with less protrusion.[2]


The Grainyhead-like (Grhl) gene family is a group of highly conserved transcription factors, which work to regulate the expression of specific target genes. Grainyhead (Grh) was originally identified in Drosophila as being implicated within development through its role of regulating numerous genetic pathways.[3] While Drosophila has only one Grh gene, there are three homologues currently known across other species (Grhl1-3).[4] It appears that all members of the Grhl gene family are involved in epidermal barrier integrity, including its formation and repair,[5][6] and are tightly regulated to prevent physical defects. The Grhl family of genes are found in a range of organisms, from humans to fish and fungi,[7][8][2] and all have similar roles to each other in regards to the developmental processes that they have a role in regulating.[8][5] This could indicate that the Grhl genes could be one of the earliest genes to arise within our genome, providing vital functions for survival of an early common ancestor.

Conservation

The Grhl gene family is tightly conserved between species across an estimated millions of years of evolution, also maintaining the binding site (AACCGGTT) on the target genes of Grhl.[9] While the presence of the Grhl genes varies between species, the functions regulated remain largely analogous.[10][2][11][12] The reason for the presence of multiple Grhl orthologues would likely be due to speciation and the evolution of species from a common ancestor over time.[4] Due to many animals possessing Grhl genes, there are many possible animal models available for research on the Grhl family. At present, the most characterized are the models of Drosophila, mouse and zebrafish. Interestingly, Grh was also identified in fungi, which lack epidermal tissue and instead utilize a cell wall.[8] This gives evidence that the formation of physical barriers across all, or a large variety of, species may have had an evolutionary ancestor that initially developed barrier formation as a result of the presence of a Grhl gene.

Orthologues

Grhl1

Grhl1 is, much like the rest of the family of genes, involved in epithelial barrier formation and wound healing while the loss of Grhl1 is often associated with the activation of the skin's immune system.[13] Knockout of grhl1 in zebrafish has shown to cause hair cell apoptosis within the inner ear which leads to sensory epithelium damage that consequently causes deafness.[14] Grhl1 may carry out its functions through regulation of downstream genetic targets such as desmosomal cadherin genes (Dsg1) and other cadherin family genes, as a reduction in Grhl1 yields similar phenotypes to that of reduced Dsg1 expression.[9] The desmosomes are the intercellular junctions within the epidermis and genes like Dsg1 regulate cadherin expression within these junctions. The development and differentiation of epidermal cells is regulated by Grhl1 in a tissue-specific manner in vertebrates, meaning that different tissues will respond differently to Grhl1 regulation.[15] In regards to other craniofacial features, such as the palate and jaw, Grhl1 does not currently have any known significant role in their development.[16]

Grhl2

Grhl2 is involved in lower jaw formation of mammals, among other craniofacial developmental processes.[17][18] It is also evolutionarily closest to Grhl1, compared to Grhl3, while still exhibiting the highly conserved functions that all Grhl genes share.[14] It also appears that Grhl2 is involved in the fusion of the facial bones and that disruption to the regulation of Grhl2 can lead to cranioschisis/split face during embryonic development, often causing death.[19][20][11] Continuing with the trend of incomplete fusion, the formation of the neural tube and abdominal wall is also regulated by Grhl2, evident by observation of incomplete closure of these structures, leading to spina bifida and thoracoabdominoschisis, following loss of Grhl2 function in mutant mice models for Grhl2.[20][11] Additionally, over-expression of Grhl2 can also lead to mice developing spina bifida, showing the delicate balance in regulation required for Grhl2.[19] Grhl2 is also related to breast cancer progression due to its ability to regulate epithelial cells and other processes such as epithelial-mesenchymal transition (EMT), although it is not known if EMT is promoted or inhibited by Grhl2.[21] However, tumour progression is more associated with the epithelial tissue phenotype.[21] Interestingly, within zebrafish there are two separate orthologues, grhl2a and grhl2b.[16] Comparing the homology of these two orthologues to the human and mice equivalent, Grhl2, showed that grhl2b had 36 out of 47 amino acids identical (77% identical), meaning it was slightly more conserved than grhl2a, which had 34 out of 47 (72% identical).[2] grhl2b loss causes apoptosis throughout the brain and the nervous system of zebrafish.[2] A similar result came from a mouse study and led to the belief that grhl2b is a key survival factor for neural cells.[22]

Grhl3

Much the same as the previous two orthologues, Grhl3 is involved in the regulation of epidermal tissue, such as the formation of the jaw, neural tube and other craniofacial features, and does so across both land and aquatic organisms.[23][12][17] Grhl3 is a downstream target of Irf6, and plays a key role in processes involving fusion during development much like Grhl2, especially so in the oral palate and spinal cord.[23] A mutation of Grhl3, that causes an increase or a decrease in expression, can lead to Van der Woude syndrome, which is characterized by phenotypes that include cleft lip and/or palate and spina bifida.[24][25] Primarily, Grhl3 appears to play a vital role for regulating the development of the craniofacial skeleton.[1] A genome-wide association study found that Grhl3 is an etiological variant for a nonsyndromic form of cleft palate, ~50% of all cleft palate cases, highlighting the level of impact that dysregulation of Grhl3 has on development.[26] Apart from the defects that are physically noticeable, Grhl3 is also expressed in the brain of mice embryos and has been shown to regulate the impulsiveness and anxiety levels of mice.[27] Furthermore, it appears that grhl3 regulates the enveloping layer of zebrafish and axial extension as well as cell size and identity during embryonic development.[5] If expression is disrupted during the early stages of disruption it will lead to severe defects that can lead to the death of the embryo before epiboly is complete.[5] Epiboly is the stage of development for select organisms, such as the xenopus, sea urchin and zebrafish, when the cells of the embryo grow and migrate to the opposite end of the yolk sac to envelop it to continue developing.

Developmental Defects

Associated defects/diseases

There are thousands of deaths a year of infants, either during or shortly after birth, and the leading cause of these deaths are congenital birth defects (CBDs), which are defined as abnormalities of the chromosomes.[28][29] In the year 2004, CBDs had been the cause of over 139,000 hospitalizations in the U.S. and had cost the community $2.6 billion in healthcare and medical supplies.[30] While some CBDs can be easily fixed by simple surgery or medication, such as cleft lip, there are still life threatening diseases that are caused by mutations to the Grhl family members or genetic pathways that they are associated with. In developing countries, where there is a large percentage of the population in poverty, families struggle to receive the necessary treatment to combat CBDs and the extent at which the quality of life is affected is continually worsening.[31] Members of the Grhl3 family are closely related to endodermal tissues and the issues that can arise from a mutation in one of the Grhl family members can include respiratory problems, loss of hearing, spina bifida and much more.[10][11] Grhl3 has been shown to be a downstream target of genes such as Fgf8 and Irf6, of which the associated pathways are involved in the aetiology of Van der Woude syndrome.[2][23]

Role of Grhl in disease

Disease What it is Grhl family member involved Reference
Anxiety and impulsiveness These factors are linked to diseases such as ADHD and numerous forms of anxiety. Grhl3 (mice) [27]
Breast cancer progression Over-expression promotes tumour growth and metastasis due to its role in regulating epithelial cell phenotype and EMT. Grhl2 (human & mice) [21]
Cleft lip/palate (Van der Woude syndrome) Incomplete fusion of the lip and/or palate, affects 1 in 700 newborns. grhl3 (mice) and Grhl2 (mice) [32][23][17]
Craniofacial defects Abnormalities in growth of facial features, such as development of the lower jaw and pharyngeal arches. Grhl2 (mice) and grhl3 (zebrafish) [12][17][18]
Deafness Loss of ability to hear sound due to loss of ability to detect and/or interpret sound waves. grhl1 (zebrafish) and Grhl2 (zebrafish) [14][33]
Disrupted locomotor development Change in movement behaviour that includes factors such as stride length, stride frequency and gait. Grhl3 (mice) [27]
Exencephaly When the brain is located outside of the skull and is usually an early stage of anencephaly. Grhl3 (mice) [10]
Midbrain-Hindbrain defects Defects in patterning and folding of the midbrain-hindbrain barrier that can lead to neural cell death. grhl2b (zebrafish) [2]
Skin barrier defects Defects in the formation of the skin during embryonic development leading to death via dehydration Grhl3 (mice) [34]
Skin cancer (squamous cell carcinoma) Increased survival and growth of squamous cells in the epidermis. Grhl3 (human & mice) [35]
Spina bifida Incomplete closure of the neural tube during development with the spinal cord exposed to varying degrees. Grhl3 (mice) [10][25][19][36][37][20]
Split face (cranioschisis) Failure of the cranium to close and leads to brain exposure, degeneration and eventual anencephaly. Grhl2 (mice) and Grhl3 (mice) [10][20][19]
Thoracoabdominoschisis Incomplete closure of the body wall, leading to opening of the thoracic and/or abdominal cavity. Grhl2 (mice) [18]
Wound healing The healing and closure of epithelial tissue after a lesion occurs, associated with cell migration within the epidermis. Grhl3 (mice) [38][34][6]

Additional information

Acknowledgements

We would like to thank those who made the opportunity of writing this article possible, Thomas Shafee from the WikiJournal of Science and my supervisor Sebastian Dworkin. It has been a great experience to be a part of.

Competing interests

We would like to declare that there are no competing interests to the authors and that raising awareness and spreading information on this topic is the main goal.

References

  1. ↑ 1.0 1.1 Goldie, Stephen J.; Arhatari, Benedicta D.; Anderson, Peter; Auden, Alana; Partridge, Darren D.; Jane, Stephen M.; Dworkin, Sebastian (2016-10-18). "Mice lacking the conserved transcription factor Grainyhead-like 3 (Grhl3) display increased apposition of the frontal and parietal bones during embryonic development". BMC Developmental Biology 16 (1). doi:10.1186/s12861-016-0136-7. ISSN 1471-213X. PMID 27756203. PMC PMC5070091. http://bmcdevbiol.biomedcentral.com/articles/10.1186/s12861-016-0136-7. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Dworkin, Sebastian; Darido, Charbel; Georgy, Smitha R.; Wilanowski, Tomasz; Srivastava, Seema; Ellett, Felix; Pase, Luke; Han, Yanchao et al. (2012-02-01). "Midbrain-hindbrain boundary patterning and morphogenesis are regulated by diverse grainy head-like 2-dependent pathways". Development 139 (3): 525–536. doi:10.1242/dev.066522. ISSN 0950-1991. PMID 22223680. https://dev.biologists.org:2083/content/139/3/525. 
  3. ↑ Bray, S. J.; Kafatos, F. C. (1991-09-01). "Developmental function of Elf-1: an essential transcription factor during embryogenesis in Drosophila.". Genes & Development 5 (9): 1672–1683. doi:10.1101/gad.5.9.1672. ISSN 0890-9369. PMID 1909284. http://genesdev.cshlp.org/content/5/9/1672. 
  4. ↑ 4.0 4.1 Traylor-Knowles, Nikki; Hansen, Ulla; Dubuc, Timothy Q; Martindale, Mark Q; Kaufman, Les; Finnerty, John R (2010). "The evolutionary diversification of LSF and Grainyhead transcription factors preceded the radiation of basal animal lineages". BMC Evolutionary Biology 10 (1): 101. doi:10.1186/1471-2148-10-101. ISSN 1471-2148. http://bmcevolbiol.biomedcentral.com/articles/10.1186/1471-2148-10-101. 
  5. ↑ 5.0 5.1 5.2 5.3 Miles, Lee B.; Darido, Charbel; Kaslin, Jan; Heath, Joan K.; Jane, Stephen M.; Dworkin, Sebastian (2017-12). "Mis-expression of grainyhead-like transcription factors in zebrafish leads to defects in enveloping layer (EVL) integrity, cellular morphogenesis and axial extension". Scientific Reports 7 (1). doi:10.1038/s41598-017-17898-7. ISSN 2045-2322. PMID 29242584. PMC PMC5730563. http://www.nature.com/articles/s41598-017-17898-7. 
  6. ↑ 6.0 6.1 Gordon, William M.; Zeller, Michael D.; Klein, Rachel H.; Swindell, William R.; Ho, Hsiang; Espetia, Francisco; Gudjonsson, Johann E.; Baldi, Pierre F. et al. (2014-10-27). "A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia". Journal of Clinical Investigation 124 (12): 5205–5218. doi:10.1172/jci77138. ISSN 0021-9738. PMID 25347468. PMC PMC4348962. http://www.jci.org/articles/view/77138. 
  7. ↑ Wilanowski, Tomasz; Tuckfield, Annabel; Cerruti, Loretta; O'Connell, Sinead; Saint, Robert; Parekh, Vishwas; Tao, Jianning; Cunningham, John M. et al. (2002-06). "A highly conserved novel family of mammalian developmental transcription factors related to Drosophila grainyhead". Mechanisms of Development 114 (1-2): 37–50. doi:10.1016/s0925-4773(02)00046-1. ISSN 0925-4773. http://linkinghub.elsevier.com/retrieve/pii/S0925477302000461. 
  8. ↑ 8.0 8.1 8.2 Paré, Adam; Kim, Myungjin; Juarez, Michelle T.; Brody, Stuart; McGinnis, William (2012-05-09). "The Functions of Grainy Head-Like Proteins in Animals and Fungi and the Evolution of Apical Extracellular Barriers". PLOS ONE 7 (5): e36254. doi:10.1371/journal.pone.0036254. ISSN 1932-6203. PMID 22590528. PMC PMC3348937. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0036254. 
  9. ↑ 9.0 9.1 Wilanowski, Tomasz; Caddy, Jacinta; Ting, Stephen B.; Hislop, Nikki R.; Cerruti, Loretta; Auden, Alana; Zhao, Lin-Lin; Asquith, Stephen et al. (2008-03-19). "Perturbed desmosomal cadherin expression in grainy head‐like 1‐null mice". The EMBO Journal 27 (6): 886–897. doi:10.1038/emboj.2008.24. ISSN 0261-4189. PMID 18288204. PMC PMC2274933. http://emboj.embopress.org/content/27/6/886. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 Ting, Stephen B; Wilanowski, Tomasz; Auden, Alana; Hall, Mark; Voss, Anne K; Thomas, Tim; Parekh, Vishwas; Cunningham, John M et al. (2003-11-09). "Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3". Nature Medicine 9 (12): 1513–1519. doi:10.1038/nm961. ISSN 1078-8956. http://www.nature.com/articles/nm961. 
  11. ↑ 11.0 11.1 11.2 11.3 Rifat, Yeliz; Parekh, Vishwas; Wilanowski, Tomasz; Hislop, Nikki R.; Auden, Alana; Ting, Stephen B.; Cunningham, John M.; Jane, Stephen M. (2010-09). "Regional neural tube closure defined by the Grainy head-like transcription factors". Developmental Biology 345 (2): 237–245. doi:10.1016/j.ydbio.2010.07.017. ISSN 0012-1606. http://linkinghub.elsevier.com/retrieve/pii/S0012160610009486. 
  12. ↑ 12.0 12.1 12.2 Dworkin, Sebastian; Simkin, Johanna; Darido, Charbel; Partridge, Darren D.; Georgy, Smitha R.; Caddy, Jacinta; Wilanowski, Tomasz; Lieschke, Graham J. et al. (2014-08). "Grainyhead-like 3 regulation of endothelin-1 in the pharyngeal endoderm is critical for growth and development of the craniofacial skeleton". Mechanisms of Development 133: 77–90. doi:10.1016/j.mod.2014.05.005. ISSN 0925-4773. http://linkinghub.elsevier.com/retrieve/pii/S092547731400029X. 
  13. ↑ Mlacki, Michal; Darido, Charbel; Jane, Stephen M.; Wilanowski, Tomasz (2014-02-20). "Loss of Grainy Head-Like 1 Is Associated with Disruption of the Epidermal Barrier and Squamous Cell Carcinoma of the Skin". PLOS ONE 9 (2): e89247. doi:10.1371/journal.pone.0089247. ISSN 1932-6203. PMID 24586629. PMC PMC3930704. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0089247. 
  14. ↑ 14.0 14.1 14.2 Liu, Fei; Yang, Fan; Wen, Danping; Xia, Wenjun; Hao, Lili; Hu, JiongJiong; Zong, Jie; Shen, Xiaofang et al. (2015). "Grhl1 deficiency affects inner ear development in zebrafish". The International Journal of Developmental Biology 59 (10-11-12): 417–423. doi:10.1387/ijdb.140230fl. ISSN 0214-6282. http://www.intjdevbiol.com/paper.php?doi=140230FL. 
  15. ↑ Tao, Jianning; Kuliyev, Emin; Wang, Xi; Li, Xiuling; Wilanowski, Tomasz; Jane, Stephen M.; Mead, Paul E.; Cunningham, John M. (2005-03-01). "BMP4-dependent expression of Xenopus Grainyhead-like 1 is essential for epidermal differentiation". Development 132 (5): 1021–1034. doi:10.1242/dev.01641. ISSN 0950-1991. PMID 15705857. http://dev.biologists.org/content/132/5/1021. 
  16. ↑ 16.0 16.1 Jnicke, Martina; Renisch, Bjrn; Hammerschmidt, Matthias (2010). "Zebrafish grainyhead-like1 is a common marker of different non-keratinocyte epidermal cell lineages, which segregate from each other in a Foxi3-dependent manner". The International Journal of Developmental Biology 54 (5): 837–850. doi:10.1387/ijdb.092877mj. ISSN 0214-6282. PMID 19757382. PMC PMC3408584. http://www.intjdevbiol.com/paper.php?doi=092877mj. 
  17. ↑ 17.0 17.1 17.2 17.3 de Vries, M.; Carpinelli, M.; Owens, H.; Sutton, Y.; Darido, C.; Auden, A.; Partridge, D.D.; Jane, S.M. et al. (2017-07). "The vital role of Grhl2 in craniofacial and palate development". Mechanisms of Development 145: S28. doi:10.1016/j.mod.2017.04.021. ISSN 0925-4773. https://linkinghub.elsevier.com/retrieve/pii/S0925477317301041. 
  18. ↑ 18.0 18.1 18.2 Pyrgaki, Christina; Liu, Aimin; Niswander, Lee (2011-05). "Grainyhead-like 2 regulates neural tube closure and adhesion molecule expression during neural fold fusion". Developmental Biology 353 (1): 38–49. doi:10.1016/j.ydbio.2011.02.027. ISSN 0012-1606. PMID 21377456. PMC PMC3114429. https://linkinghub.elsevier.com/retrieve/pii/S0012160611001448. 
  19. ↑ 19.0 19.1 19.2 19.3 Brouns, Madeleine R.; De Castro, Sandra C.P.; Terwindt-Rouwenhorst, Els A.; Massa, Valentina; Hekking, Johan W.; Hirst, Caroline S.; Savery, Dawn; Munts, Chantal et al. (2011-04-15). "Over-expression of Grhl2 causes spina bifida in the Axial defects mutant mouse". Human Molecular Genetics 20 (8): 1536–1546. doi:10.1093/hmg/ddr031. ISSN 1460-2083. https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddr031. 
  20. ↑ 20.0 20.1 20.2 20.3 Werth, M.; Walentin, K.; Aue, A.; Schonheit, J.; Wuebken, A.; Pode-Shakked, N.; Vilianovitch, L.; Erdmann, B. et al. (2010-11-15). "The transcription factor grainyhead-like 2 regulates the molecular composition of the epithelial apical junctional complex". Development 137 (22): 3835–3845. doi:10.1242/dev.055483. ISSN 0950-1991. http://dev.biologists.org/cgi/doi/10.1242/dev.055483. 
  21. ↑ 21.0 21.1 21.2 Xiang, Xiaoyu; Deng, ZhongBin; Zhuang, Xiaoying; Ju, Songwen; Mu, Jingyao; Jiang, Hong; Zhang, Lifeng; Yan, Jun et al. (2012-12-17). "Grhl2 Determines the Epithelial Phenotype of Breast Cancers and Promotes Tumor Progression". PLOS ONE 7 (12): e50781. doi:10.1371/journal.pone.0050781. ISSN 1932-6203. PMID 23284647. PMC PMC3524252. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050781. 
  22. ↑ Menke, Chelsea; Cionni, Megan; Siggers, Trevor; Bulyk, Martha L.; Beier, David R.; Stottmann, Rolf W. (2015-07-22). "Grhl2is required in nonneural tissues for neural progenitor survival and forebrain development". genesis 53 (9): 573–582. doi:10.1002/dvg.22875. ISSN 1526-954X. PMID 26177923. PMC PMC4713386. https://onlinelibrary.wiley.com/doi/abs/10.1002/dvg.22875. 
  23. ↑ 23.0 23.1 23.2 23.3 de la Garza, Gabriel; Schleiffarth, Jack Robert; Dunnwald, Martine; Mankad, Anuj; Weirather, Jason L.; Bonde, Gregory; Butcher, Stephen; Mansour, Tamer A. et al. (2013-01). "Interferon Regulatory Factor 6 Promotes Differentiation of the Periderm by Activating Expression of Grainyhead-Like 3". Journal of Investigative Dermatology 133 (1): 68–77. doi:10.1038/jid.2012.269. ISSN 0022-202X. PMID 22931925. PMC PMC3541433. http://linkinghub.elsevier.com/retrieve/pii/S0022202X15359534. 
  24. ↑ Peyrard-Janvid, Myriam; Leslie, Elizabeth J.; Kousa, Youssef A.; Smith, Tiffany L.; Dunnwald, Martine; Magnusson, Måns; Lentz, Brian A.; Unneberg, Per et al. (2014-01). "Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development". The American Journal of Human Genetics 94 (1): 23–32. doi:10.1016/j.ajhg.2013.11.009. ISSN 0002-9297. PMID 24360809. PMC PMC3882735. http://linkinghub.elsevier.com/retrieve/pii/S0002929713005247. 
  25. ↑ 25.0 25.1 De Castro, Sandra C P; Gustavsson, Peter; Marshall, Abigail R; Gordon, William M; Galea, Gabriel; Nikolopoulou, Evanthia; Savery, Dawn; Rolo, Ana et al. (2018-09-17). "Overexpression of Grainyhead-like 3 causes spina bifida and interacts genetically with mutant alleles of Grhl2 and Vangl2 in mice". Human Molecular Genetics. doi:10.1093/hmg/ddy313. ISSN 0964-6906. PMID 30189017. PMC PMC6276835. https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddy313/5090855. 
  26. ↑ Leslie, Elizabeth J.; Liu, Huan; Carlson, Jenna C.; Shaffer, John R.; Feingold, Eleanor; Wehby, George; Laurie, Cecelia A.; Jain, Deepti et al. (2016-04). "A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3". The American Journal of Human Genetics 98 (4): 744–754. doi:10.1016/j.ajhg.2016.02.014. ISSN 0002-9297. PMID 27018472. PMC PMC4833215. https://linkinghub.elsevier.com/retrieve/pii/S0002929716000653. 
  27. ↑ 27.0 27.1 27.2 Dworkin, Sebastian; Auden, Alana; Partridge, Darren D.; Daglas, Maria; Medcalf, Robert L.; Mantamadiotis, Theo; Georgy, Smitha R.; Darido, Charbel et al. (2017-02-03). "Grainyhead-like 3 (Grhl3) deficiency in brain leads to altered locomotor activity and decreased anxiety-like behaviors in aged mice". Developmental Neurobiology 77 (6): 775–788. doi:10.1002/dneu.22469. ISSN 1932-8451. http://doi.wiley.com/10.1002/dneu.22469. 
  28. ↑ Murphy, Sherry L.; Mathews, T. J.; Martin, Joyce A.; Minkovitz, Cynthia S.; Strobino, Donna M. (2017-06-01). "Annual Summary of Vital Statistics: 2013–2014". Pediatrics 139 (6): e20163239. doi:10.1542/peds.2016-3239. ISSN 0031-4005. PMID 28814547. http://pediatrics.aappublications.org/content/139/6/e20163239. 
  29. ↑ J., Mathews, T.; F., MacDorman, Marian; E., Thoma, Marie (2015-08-06). Infant mortality statistics from the 2013 period linked birth/infant death data set (in en). 64. https://stacks.cdc.gov/view/cdc/32752. 
  30. ↑ Russo, C.A., & Elixhauser, A. (2007). Hospitalizations for birth defects, 2004. HCUP Statistical Brief #24. U.S. agency for healthcare, research and quality. Retrieved from http://www.hcup-us.ahrq.gov/reports/statbriefs/sb24.pdf
  31. ↑ Raposo-Amaral, Cassio Eduardo; Raposo-Amaral, Cesar Augusto (2012-01). "Changing Face of Cleft Care". Journal of Craniofacial Surgery 23 (1): 206–209. doi:10.1097/scs.0b013e318241ae70. ISSN 1049-2275. http://pt.wkhealth.com/pt/re/lwwgateway/landingpage.htm;jsessionid=bbsQGQ9rQLfQpvNTQL7k2NQrc44x2L8kz54yJLKhSMvJpX1Qp6ZQ!579070261!181195629!8091!-1?sid=WKPTLP:landingpage&an=00001665-201201000-00050. 
  32. ↑ Rahimov, Fedik; Jugessur, Astanand; Murray, Jeffrey C. (2012-01). "Genetics of Nonsyndromic Orofacial Clefts". The Cleft Palate-Craniofacial Journal 49 (1): 73–91. doi:10.1597/10-178. ISSN 1055-6656. PMID 21545302. PMC PMC3437188. https://journals.sagepub.com/action/captchaChallenge?redirectUri=%2Fdoi%2Ffull%2F10.1597%2F10-178. 
  33. ↑ Han, Yanchao; Mu, Yu; Li, Xiaoquan; Xu, Pengfei; Tong, Jingyuan; Liu, Zhaoting; Ma, Tingting; Zeng, Guodong et al. (2011-08-15). "Grhl2 deficiency impairs otic development and hearing ability in a zebrafish model of the progressive dominant hearing loss DFNA28". Human Molecular Genetics 20 (16): 3213–3226. doi:10.1093/hmg/ddr234. ISSN 1460-2083. https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddr234. 
  34. ↑ 34.0 34.1 Ting, Stephen B.; Caddy, Jacinta; Wilanowski, Tomasz; Auden, Alana; Cunningham, John M.; Elias, Peter M.; Holleran, Walter M.; Jane, Stephen M. (2005-4). "The Epidermis of Grhl3-Null Mice Displays Altered Lipid Processing and Cellular Hyperproliferation". Organogenesis 2 (2): 33–35. doi:10.4161/org.2.2.2167. ISSN 1547-6278. http://www.tandfonline.com/doi/abs/10.4161/org.2.2.2167. 
  35. ↑ Darido, Charbel; Georgy, Smitha R.; Wilanowski, Tomasz; Dworkin, Sebastian; Auden, Alana; Zhao, Quan; Rank, Gerhard; Srivastava, Seema et al. (2011-11). "Targeting of the Tumor Suppressor GRHL3 by a miR-21-Dependent Proto-Oncogenic Network Results in PTEN Loss and Tumorigenesis". Cancer Cell 20 (5): 635–648. doi:10.1016/j.ccr.2011.10.014. ISSN 1535-6108. https://linkinghub.elsevier.com/retrieve/pii/S1535610811003977. 
  36. ↑ Gustavsson, Peter; Greene, Nicholas D.E.; Lad, Dina; Pauws, Erwin; de Castro, Sandra C.P.; Stanier, Philip; Copp, Andrew J. (2007-11-01). "Increased expression of Grainyhead-like-3 rescues spina bifida in a folate-resistant mouse model". Human Molecular Genetics 16 (21): 2640–2646. doi:10.1093/hmg/ddm221. ISSN 1460-2083. https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddm221. 
  37. ↑ Yu, Zhengquan; Lin, Kevin K.; Bhandari, Ambica; Spencer, Joel A.; Xu, Xiaoman; Wang, Ning; Lu, Zhongxian; Gill, Gordon N. et al. (2006-11). "The Grainyhead-like epithelial transactivator Get-1/Grhl3 regulates epidermal terminal differentiation and interacts functionally with LMO4". Developmental Biology 299 (1): 122–136. doi:10.1016/j.ydbio.2006.07.015. https://linkinghub.elsevier.com/retrieve/pii/S0012160606009997. 
  38. ↑ Hislop, Nikki R.; Caddy, Jacinta; Ting, Stephen B.; Auden, Alana; Vasudevan, Sumitha; King, Sarah L.; Lindeman, Geoffrey J.; Visvader, Jane E. et al. (2008-09). "Grhl3 and Lmo4 play coordinate roles in epidermal migration". Developmental Biology 321 (1): 263–272. doi:10.1016/j.ydbio.2008.06.026. ISSN 0012-1606. https://linkinghub.elsevier.com/retrieve/pii/S0012160608010178. 
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