Embryonic development is a time- and space-ordered series of gene interactions, each in turn designating polarity, germ-layer identity, and individual cell type differentiation. Critical to our study is to determine how these time- and space-restricted instructions are signaled and received during morphogenesis of different phenotypes derived from the first branchial arch. Our previous studies on the regulation of first branchial arch morphogenesis have identical critical components of a well-accepted hierarchy of growth factors and their downstream transcription factors, which regulates the expression of genes responsible for determining cell phenotypes during embryogenesis. Here, we propose to test the hypothesis that TGF-beta signals converge on specific Smads which may alter the expression of transcription factors Msx1, Msx2 and Lef1 resulting in particular phenotypes during the morphogenesis of first branchial arch. TGF-beta ligands are expressed in a time- and tissue-specific manner and are important in regulation of tooth and Meckel's cartilage formation. Both time- and tissue-specific manner and are important in regulation of tooth and Meckel's cartilage formation. Both TGF-beta type I and type II (IR & IIR) receptors as well as their downstream intracellular mediators S Smad2, 3, 4 and 7 are required constituents of the TGF-beta signaling pathway. Activated Smads may regulate transcription factor expression, affecting target-gene transcriptional status. Our preliminary data show that TGF-beta cognate receptors, TGF-beta signaling pathway specific Smads and transcriptional factors Msx1, Msx2 & Lef1 are critical components in regulating first branchial arch morphogenesis.
Our specific aims are: (1) to determine and compare the temporal and spatial expression of TGF-beta, IR, IIR, Smad2, Smad3, Smad4, Smad7 and transcription factors (Msx1,2 and Lef1) during the formation of tooth and Meckel's cartilage both in vivo and in vitro. (2) to test the function of TGF-beta IR, IIR, Smad2, Smad3 and Smad4 signaling in regulating first branchial arch morphogenesis using gain-of-function and loss of function experiments. (3) to determine the impact of TGF-beta signaling on the expression of Msx1, Msx2 and Lef1 using implantation of beads being different TGF-beta isoforms, assess the morphological changes, and evaluate the expression of Msx1, Msx2 and Lef1, using both wild type and readily available Msx1, Msx1 transgenic animals. The molecular mechanism of TGF-beta down-regulation of Msx1 and 2 expression will also be explored. (4) to define the function of TGF- beta signaling inhibitory molecule Smad7 and its regulatory effect on the expression of Msx1, Msx2 and Lef1 as well as other growth factors (EGF, PDGF-AA and FGF). Ultimately , this study will advance our understanding of how the TGF-beta signaling cascade guides normal craniofacial development and his disruption in the TGF-beta signaling pathway can lead to craniofacial malformations.
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