The neural circuits underlying perception and behavior are assembled during development through intricate and coordinated processes that include neurogenesis and migration, axon and dendrite extension and arborization and synapse formation. In turn, conserved genetic programs orchestrate these dynamic developmental processes. While much progress has been made in identifying genes that are important for neural function, the mechanisms linking the action of gene products to the assembly of neural architecture and to function are poorly understood. To address this important question, we have generated zebrafish mutants and transgenic lines for several ?-pcdhs, evolutionarily conserved homophilic cell adhesion molecules that are strongly expressed in the developing nervous system. We show that ?-pcdhs are expressed within radial columns of neurons in the developing zebrafish optic tectum, and that the neurons within these columns are siblings derived from one or a small number of progenitors. Loss of pcdh19 degrades the columnar organization of pcdh19-expressing neurons, indicating that protocadherin function is required for column maintenance. Moreover, pcdh19 mutants exhibit defects in visually guided behaviors. This proposal tests the hypothesis that the shared inheritance of a ?-pcdh confers an identity to a column of neurons, and that differential expression ?-pcdhs defines a code for organizing tectal circuitry and is essential for neural function and behavior. Specifically, we will map the 3D distribution of neurons expressing individual ?-pcdhs, use in vivo timelapse to determine the cellular roles of ?-pcdhs during column formation, and use in vivo calcium imaging to determine the effects of ?-pcdh loss on the development of neural activity patterns. This study will shed light on a fundamental aspect of neural organization and generate essential new insights into the relationships between genes, the development of neural architecture and the origins of a range of neurodevelopmental disorders attributed to members of the protocadherin subfamily of cell adhesion molecules.
This project is relevant to human health, as mutations in human PCDH19 cause a female-limited form of epilepsy and are associated with an increased incidence of other brain disorders. In addition, other members of this family (e.g., pcdh7, pcdh9 and pcdh17) have been implicated in autism or schizophrenia. Understanding the function of pcdh19 during neural development is essential for the rational design of therapeutic strategies for PCDH19 female-limited epilepsy, and could provide important insights into the origins of other neurodevelopmental disorders.
|Jontes, James D (2018) The Cadherin Superfamily in Neural Circuit Assembly. Cold Spring Harb Perspect Biol 10:|
|Light, Sarah E W; Jontes, James D (2017) ?-Protocadherins: Organizers of neural circuit assembly. Semin Cell Dev Biol 69:83-90|