Expression and function of Wnt, TNF and TGF-beta superfamily receptors in developing neurons

Doctoral thesis English OPEN
Teixeira, Dania Sofia da
  • Subject:
    mesheuropmc: nervous system

In the developing peripheral nervous system, neuronal survival and axonal growth are regulated by a variety of factors, the most extensively studied of which are secreted neurotrophic factors. To identify additional candidate molecules involved in regulating these aspects of neuronal development, I carried out a PCR screen for the expression of transcripts encoding receptors and selected ligands of three important superfamilies ligands and receptors (Wnt, TGF-beta and TNF) over a broad range of developmental ages in three experimentally tractable populations of PNS neurons of mice (superior cervical ganglion, nodose ganglion and trigeminal ganglion). From these screening results I selected one member of the TGF-beta superfamily (growth differentiation factor 5, GDF5), and one of the TNF receptor superfamily (B Cell Maturation Antigen, BCMA). These studies have revealed that GDF5 is synthesized in sympathetic targets and promotes sympathetic axon growth and branching independently of NGF when these axons are ramifying in their distal targets. Mice lacking GDF5 have major deficiencies in sympathetic innervation without loss of neurons, indicating that target-derived GDF5 is essential for establishing appropriate tissue innervation during development. Function blocking antibodies against BCMA and one of its ligands, BAFF, markedly impair the ability of NGF to promote the survival of cultured sympathetic neurons from the SCG ganglion at the postnatal age of PO. Similarly, blocking the functions of BCMA and its other ligand, TACI, also leads to impaired survival, but at the earlier age of El 5. These findings reveal novel regulators of axonal growth and neuronal survival in developing peripheral nervous system.
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