The ultimate objective of my laboratory is to decipher the molecular basis of neural/epidermal induction and patterning in the vertebrate embryo. Our previous work has shown that one of the earliest steps in the determination of neural fate requires inhibition of BMP/GDF signaling. BMP/GDF ligands belong to the TGF_ signaling pathway. This established the concept of the """"""""default model"""""""" of neural induction. The inhibition of BMP/GDF signaling occurs in vivo in the dorsal ectoderm during gastrulation, and is mediated by secreted factors emanating from the organizer (dorsal mesoderm). As a direct result of this inhibition, dorsal ectoderm forms neural tissue. In the ventral ectoderm, where the BMP/GDF pathway is not inhibited, signaling by these factors via signal transducers Smad1/5/8 leads to the induction of epidermis. In this repackaged competitive renewal, I propose to continue our efforts in dissecting the TGF_ signaling pathways that underlie ectodermal patterning at the molecular, cellular and embryological level by focusing on the characterization of an unexpected inhibitor of the pathway, that was discovered during our previous round of funding: TAB3 (TAK1- Binding-protein-3). TAK1 (TGFb-Activated-Kinase-1), and TAB3 transduce BMP/GDF signal in Smad independent manner, and thus links the BMP pathway to the MAP kinase pathway.
Two specific aims are proposed. The first targets the characterization of binding partners of TAB3, which transduces BMP signals in a Smad independent manner. The second specific aim, targets the characterization of the cellular and embryological functions of TAB3-binding partners. TAB3 links the BMP pathway to the MAP kinase pathway. As the BMP pathway is involved in large numbers of biological activities, an in-depth molecular understanding of the pathway will have a direct impact on many different fields in addition to molecular embryology.
This proposal targets the characterization of the role of signaling pathways in early vertebrate embryonic development. These signaling pathways are involved in the establishment of discreet cell fates. Among different signaling pathways, members of the TGFb family have been evolutionarily conserved from worms to humans, and they span a large range of biological activity, both during embryogenesis and during adulthood. Mutations disrupting these pathways in humans are the cause of various forms of diseases including developmental disorders and cancer. For example, mutations of one of the genes proposed to be studied here, BMP15, leads to ovarian failure, early onset of menopause and infertility. Thus, findings derived from these studies will extend beyond their relevance to embryology and enrich our knowledge about these important signaling pathways reiterated again and again in different tissues and cell types throughout life.
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