Craniofacial related birth defects account for 1/3rd of all congenital anomalies. Defects in neural crest cells (NCC) cause most of these disorders;however, the signaling pathways involved in craniofacial morphogenesis are poorly understood. Therefore, knowledge of the molecular mechanisms of neural crest development is necessary to understand human craniofacial disorders. Our long-term goal is to identify the regulatory pathways that instruct NCC morphogenesis. The objective of this application is to determine the molecular and genetic role of the TFII-I transcription factor in craniofacial development. Deletion of the Gtf2i allele, which encodes this protein causes craniofacial defects in mice. TFII-I regulates the transcription of target genes via interactions with histone deacetylases and Smad2 and is expressed in neural crest-derived tissues. We hypothesize that 1 of the roles of TFII-I is to control signaling cascades critical for neural crest morphogenesis. We, therefore, propose an in depth analysis of Gtf2i to understand its role during neural crest development. First, molecular and cellular changes underlying craniofacial defects will be analyzed in mutant embryos. Second, a set of downstream target genes regulated by TFII-I in cranial NCC will be identified using microarray and chromatin immunoprecipitation analysis. Third, the Gtf2i allele will be abrogated in the NCC lineage with the conditional Cre/LoxP recombination system. The outcome of the proposed research will allow us to identify the TFII-l-dependent genes and signaling pathways involved in the morphogenesis of neural crest-derived structures. These studies will provide a better understanding of craniofacial genetic pathways and pathogenesis of human birth defects.
| Enkhmandakh, Badam; Stoddard, Chris; Mack, Kris et al. (2016) Generation of a mouse model for a conditional inactivation of Gtf2i allele. Genesis 54:407-12 |
| Makeyev, Aleksandr V; Enkhmandakh, Badam; Hong, Seung-Hyun et al. (2012) Diversity and complexity in chromatin recognition by TFII-I transcription factors in pluripotent embryonic stem cells and embryonic tissues. PLoS One 7:e44443 |
| Bayarsaihan, Dashzeveg; Makeyev, Aleksandr V; Enkhmandakh, Badam (2012) Epigenetic modulation by TFII-I during embryonic stem cell differentiation. J Cell Biochem 113:3056-60 |
| Chimge, Nyam-Osor; Makeyev, Aleksandr V; Waigel, Sabine J et al. (2012) PI3K/Akt-dependent functions of TFII-I transcription factors in mouse embryonic stem cells. J Cell Biochem 113:1122-31 |
| Bayarsaihan, D (2011) Epigenetic mechanisms in inflammation. J Dent Res 90:9-17 |
| Makeyev, Aleksandr V; Bayarsaihan, Dashzeveg (2011) Molecular basis of Williams-Beuren syndrome: TFII-I regulated targets involved in craniofacial development. Cleft Palate Craniofac J 48:109-16 |
| Chimge, Nyam-Osor; Bayarsaihan, Dashzeveg (2010) Generation of neural crest progenitors from human embryonic stem cells. J Exp Zool B Mol Dev Evol 314:95-103 |
| Makeyev, Aleksandr V; Bayarsaihan, Dashzeveg (2009) Alternative splicing and promoter use in TFII-I genes. Gene 433:16-25 |
| Makeyev, Aleksandr V; Bayarsaihan, Dashzeveg (2009) New TFII-I family target genes involved in embryonic development. Biochem Biophys Res Commun 386:554-8 |
| Enkhmandakh, Badam; Makeyev, Aleksandr V; Erdenechimeg, Lkhamsuren et al. (2009) Essential functions of the Williams-Beuren syndrome-associated TFII-I genes in embryonic development. Proc Natl Acad Sci U S A 106:181-6 |
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