? ? Cranial Neural crest cells (CNC) are an embryonic population of multipotent precursor cells that give rise to craniofacial cartilage and bone in the head. Understanding the mechanisms responsible for specification, migration and differentiation of the CNC involves characterizing multiple signaling pathways that converge to regulate expression of effector genes. Recently, we have shown that alk8, a novel Type I TGF-beta family member receptor, participates in Bmp signaling pathways and influences mediolateral positioning of CNC's and dorsoventral (DV) patterning of pharyngeal arch cartilages. The goal of this proposal is to define the role of Alk8 and Bmp signaling in pharyngeal arch morphogenesis and potential roles in specification of the neural crest. Zebrafish are an ideal vertebrate model for these studies because the embryos are transparent, easy to genetically manipulate, and the craniofacial skeleton is well formed within 5 days.
Specific Aim 1 will characterize the temporospatial expression patterns of Alk8. These studies will be coupled with promoter analysis to determine regulatory elements driving tissue specific and/or temporally restricted Alk8 expression.
Specific Aim 2, mosaic analysis, will determine the cell autonomous/non-autonomous effect that Alk8 exerts on the neural crest.
Specific Aim 3 will examine pharyngula stages of embryogenesis to determine if apoptosis or later chondrogenic defects contribute to defects in cartilage formation. To place Alk8 signals into the larger context of the multiple pathways regulating arch development, we will perform a screen for alk8 downstream signaling components that are potential candidates for CNC specific signaling events. Finally, we hypothesize that Alk8 affects specification of the CNC at an early stage and is therefore likely to affect other NCC derivatives as well. We therefore propose to examine the influence of Alk8 on other NCC derivatives, including pigment cells and the peripheral nervous system to identify defects in their specification and/or patterning. These experiments will lend insight into the mechanisms specifying the neural crest, and will aid in development of therapies for congenital disorders such as Treacher Collins syndrome, Hirschsprung's disease and Cleidocranial dysplasia.
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