Characterization of TGFbeta signaling in the nervous system.
Published: 2005
Language: eng
Number of pages: 165
Description: Genetic studies on a Drosophila TGFbeta receptor Wishful thinking (Wit) that is most closely related to the mammalian BMP type II receptor (BMPRII), showed that Wit-mediated BMP signals are essential during neural development. To study Wit-mediated signaling, I used a biochemical approach to establish the Wit ligand-binding repertoire and to examine its downstream signaling. These studies revealed the direct binding of BMP7 and BMP4, the mammalian homologues of Drosophila Glass Bottom Boat (Gbb) and Decapentaplegic (dpp), respectively, to Wit. In addition, co-expression of Wit and the type I receptor, Thick veins (Tkv), induces BMP-specific Smad, MAD, phosphorylation. Furthermore, both myoglianin and its most closely related mammalian ligand, myostatin, both bind to a Wit and Baboon (Babo; an activin type I receptor) receptor complex and activate TGFbeta/activin-like signaling. Thus, Wit binds multiple ligands to activate both BMP and TGFbeta-like pathways.The transforming growth factor beta (TGFbeta) family of ligands, encompassing TGFbetas, Activins and Bone Morphogenetic Proteins (BMPs) regulate numerous biological processes including neural development yet many of the receptor-mediated signaling events are unclear. Here I present studies that examine this area and provide insight into their cellular roles.BMP7 affects dendritic morphogenesis that is critical for neural function. While dendritic morphogenesis is driven by cytoskeletal reorganization, a neurally expressed LIM kinase 1 (LIMK1) phosphorylates and inhibits actin-binding protein cofilin, and thus may be a key regulator of the process. Since BMPRII is widely expressed in the developing nervous system and contains a C-terminal domain that is conserved in Wit, I addressed whether BMPRII is involved in the regulation of dendritic morphogenesis, possibly via the C-terminal region. The work presented here demonstrates that LIMK1 colocalizes with BMPRII in the tips of neurites and directly binds to the C-terminal region of the receptor. Furthermore, this interaction is required for BMP7-induced dendritic outgrowth in cortical neurons and synergizes with the Rho GTPase, Cdc42, to activate LIMK1 catalytic activity. Thus, this study defines a Smad-independent pathway that directly links the BMP receptor to regulation of actin dynamics and provides insight into how extracellular signals modulate LIMK1 activity to permit fine spatial control over cytoskeletal remodeling.
Notes: Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5241.

Thesis (Ph.D.)--University of Toronto, 2005.

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