Craniofacial abnornialities involving the first branchial arch derivatives, including jaw,,palate, and teeth, are a major class of birth defects in humans. Understanding the molecular genetic mechanisms behind craniofacial development is vital to devising innovative methods for diagnosis, prevention, and treatment of human defects. The long-term goal of niy research is to characterize the transcriptional network that governs development of the first branchial arch, by identifying transcription factors and cis-regulatory elements important in this process, and determining th^eir hierarchic^ relationship. Lhx6 and Lhx3 genes, encoding homeodomain transcription factors, are major regulators of first branchial arch development;mouse mutants lacking the activities of both Lhx6 and Lhx8 are born with cleft secondary palate and no molars. Specifically, I found that the Lhx genes are essential for the initial steps of molar and secondary palate development. Two crucial questions remain on the function and regulation of Lhx genes in craniofacial development: 1) what is the molecular and cellular mechanisms of Lhx function during the initiation of tooth and palate development?, and 2) what are the upstream factprs that regulate the expression of the Lhx genes in the first branchial arch? My research during'ROO phase will address these questions using mouse mutant models as well as biochemistry and molecular biology methods. The results of this project will provide critical information on how disruption in Lhx6 and Lhx8 function and expression can contribute to human craniofacial defects.
Craniofacial abnormalities are one of the most common birth defects in humans. The proposed project will advance our knovi/Iedge of the molecular genetic causes of these defects, which is crucial to devising innovative methods for diagnosis, prevention and treatment.
|Cesario, Jeffry M; Almaidhan, Asma A; Jeong, Juhee (2016) Expression of forkhead box transcription factor genes Foxp1 and Foxp2 during jaw development. Gene Expr Patterns 20:111-9|
|Cesario, Jeffry M; Landin Malt, Andre; Deacon, Lindsay J et al. (2015) Lhx6 and Lhx8 promote palate development through negative regulation of a cell cycle inhibitor gene, p57Kip2. Hum Mol Genet 24:5024-39|
|Almaidhan, Asma; Cesario, Jeffry; Landin Malt, Andre et al. (2014) Neural crest-specific deletion of Ldb1 leads to cleft secondary palate with impaired palatal shelf elevation. BMC Dev Biol 14:3|
|Landin Malt, André; Cesario, Jeffry M; Tang, Zuojian et al. (2014) Identification of a face enhancer reveals direct regulation of LIM homeobox 8 (Lhx8) by wingless-int (WNT)/?-catenin signaling. J Biol Chem 289:30289-301|
|Jeong, Juhee; Cesario, Jeffry; Zhao, Yangu et al. (2012) Cleft palate defect of Dlx1/2-/- mutant mice is caused by lack of vertical outgrowth in the posterior palate. Dev Dyn 241:1757-69|