Disrupted Cilia Signaling in Tuberous Sclerosis Complex
Abstract
The emergence of cerebral cortex occurs as a result of coordinated unfolding of neural progenitor formation, neurogenesis, neuronal migration, post-migratory neuronal differentiation and connectivity. Mutations in TSC1 or TSC2 lead to tuberous sclerosis complex (TSC) characterized by aberrant cortical development. Efficient intracellular response to extracellular signaling proteins is fundamental to coordinate the multitude of cellular events underlying the normal formation of cerebral cortex. Primary cilia, the microtubule-based, slender projections found on virtually every eukaryotic cell, including cortical progenitors and neurons are emerging as essential conveyors of signal transduction underlying major cell functions. Disrupted cilia function in humans results in profound cortical abnormalities and intellectual disabilities. However, the essential roles of primary cilia dysfunction in tuberous sclerosis complex (TSC) related cerebral cortical development are mostly unknown. Thus, a critical question to be answered is what role cilia function or dysfunction plays in the development TSC pathology in cerebral cortex. Here, we will explore (1) how primary cilia signaling in cortical progenitors and newborn cortical neurons regulates TSC1/2 expression and function, (2) how disruptions in this process may contribute to the emergence of TSC phenotype, and (3) how manipulation of cilia signaling could be used as a therapeutic avenue to ameliorate TSC deficits. Towards this goal, we aim to systematically define the functions of primary cilia in TSC models of the cerebral cortex using cilia-specific Arl13b signaling as a molecular model, delineate the cilia-dependent molecular mechanisms that regulate TSC1/2 functions, and identify the developmental disruptions underlying brain abnormalities in TSC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2018
- Accession Number
- AD1091516
Entities
People
- Eva S. Anton
Organizations
- University of North Carolina at Chapel Hill