Role of Exo Vesicular Hedgehog and its associated partners in neuronal patterning

Abstract

Sonic Hedgehog (Shh) is a pivotal morphogen involved in the patterning of various embryonic tissues, including the developing spinal cord and is conserved across species. In the developing neural tube, Shh specifies the ventral inter-neurons and motor neurons; Shh is also involved in progenitor proliferation during growth of the neural tube. How these distinct outcomes are specified has remained elusive. It was previously identified that Shh is secreted on at least two different types of exosomes. The current study unravels that the different signalling roles of Shh are partitioned on these distinct Shh-exosomal pools. In this study, using neural explant assay it is demonstrated that the dense exosomal pool of Shh (Shh-P150) drives the Smoothened (Smo)-Gli signalling axis and is involved in ventral neural progenitor specification. While the newly identified lighter exosomal pool of Shh (Shh-P450) activates the Smoothened mediated Gand#945;i signalling, that enhances the proliferation of neural progenitor cells. This work further clarifies that secretion of these distinct exosomes are modulated by the late endosomal regulator, Rab7. I find that loss of Rab7 causes reduced secretion of Shh-P150, which further affects the ventral neural tube patterning but Shh-P450, the proliferative pool, secretion remains unaffected. My thesis demonstrates the cellular mechanisms involved in sorting and secretion of Shh on distinct exosomal pools (P150 or P450). Overall this study unravels the intricate cellular processes that allow differently packaged Shh to function efficiently as a morphogen and a mitogen during neural tube development. newline