Microglia colonization and maintenance in zebrafish

Abstract

Microglia, tissue resident macrophages in the CNS, are involved in diverse biological processes such as removing apoptotic neurons, pruning synaptic formation, regulating neuronal activity and directing cerebral vasculature development. Aberrant activation of microglia has been constantly observed during neurological disorders. Although microglia have been extensively studied in the past decades, many aspects such as the CNS colonization and self-maintenance of microglia remains elusive. Taking advantage of live imaging as well as genetic manipulation of zebrafish, the study of this thesis reveals that microglial precursors colonize the zebrafish brain via two major routes, basal lateral entry and ventral midbrain entry. The colonization of the brain by microglia is independent of circulation and is induced by apoptotic death of neurons, which naturally occurs during neurogenesis. Subsequent molecular studies demonstrated that the apoptotic neural death-induced microglia colonization of the brain is mediated lysophospholipid (LPC and LPA) through two G protein coupled receptors, gpr132b and lpar1, which are highly enriched on microglia. To uncover molecular determinants involved in the maintenance of microglia, a large-scale forward genetic screening has been carried out and a temperature sensitive mutant zebrafish displaying microglia absent phenotype was identified. Positional cloning revealed that the responsible lesion gene is nlrc3-like which belongs to nod like receptor family. Further investigation demonstrated that nlrc3-like deficient microglia undergo inflammatory associated cell death partially dependent on Myd88.

Date of Award	2017
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology