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TGF-ß SIGNALING AND ITS FUNCTIONAL SIGNIFICANCE IN REGULATING THE FATE OF CRANIAL NEURAL CREST CELLS

Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033;

View larger version (34K): [in a new window]   Figure 1. TGF-ß ligand binding to the heteromeric receptor complex induces phosphorylation of the type I receptors by the constitutively active type II receptors. Receptor activation then results in phosphorylation of receptor-associated Smads (Smad2 and Smad3). The phosphorylated Smads may then cooperate with Smad4, which is not associated with the receptor or phosphorylated by it. The cooperativity of receptor-associated Smads with Smad4 may be a general prerequisite for receptor signaling. The activated, heteromeric Smads complex will translocate into the nucleus to function as a transcriptional regulator, which can regulate the expression of transcription factors. Smad7 associates stably with the TGF-ß receptor complex, but is not phosphorylated upon TGF-ß stimulation. TGF-ß-mediated phosphorylation of Smad2 and Smad3 is inhibited by Smad7, indicating the antagonistic effect of Smad7 in regulating the TGF-ß signaling pathway.

View larger version (33K): [in a new window]   Figure 2. Differentiation of cranial neural crest cells. As CNC cells migrate into the craniofacial region, these ectomesenchymal progenitors may give rise to an array of tissue types, such as odontoblasts, chondroblasts, osteoblasts, etc. Both ectoderm and endoderm of the branchial arch provide signaling instructions for the fate specification of these progenitor cells. CNC cells also contribute to the formation of neural tissues, such as sensory neurons and cranial nerve ganglia.

View larger version (96K): [in a new window]   Figure 3. The expression of Msx1 is inhibited by TGF-ß signaling. E11 mandibular explant (cultured for 2 days in serumless, chemically defined medium) shows proper Msx1 expression (double arrow) in the future molar tooth region adjacent to the BSA-bearing (0.1% bovine serum albumin) bead (A) on the left side of the explant. Bead (B) bearing TGF-ß2 (10 µg/mL) significantly inhibits the expression of Msx1 (double arrow) on the right side of the mandibular explant.