nlrc3-like deficiency triggers pycard-dependent microglia pyroptosis in zebrafish

Abstract

Microglia are resident macrophages in central nervous system (CNS) playing pivotal roles in supporting neuron development by pruning synapses and secreting neuron trophic factors as well as keeping brain homeostasis by clearing dead neurons and Aβ plaques. It is well accepted that microglia are highly associated with Alzheimer’s disease, Parkinson’s disease and prion disease. Comprehensive and thorough understanding of microglial development and function is beneficial to realize the causes of neurodegenerative diseases and seek for novel strategies for treatment. However, the molecular mechanism of how microglia develop and maintain homeostasis in brain is still largely unknown. Here, in our study, a temperature sensitive mutant named puer was identified by ENU-induced forward genetic screening. Genetic mapping and mRNA rescue assays confirmed that nlrc3-like carrying a T to A mutation in coding sequence, a member of NOD-like receptor family, is the causative gene to microglia defect. Further time-lapse imaging with temperature shift assays illustrated that microglia undergo pyroptotic cell death and inflammatory activation after colonization into brain. Besides, disruption of pycard partially prevents the microglia cell death in puer mutant under restricted temperature. Taken together, nlrc3-like maintains microglia homeostasis by preventing them from pycard-dependent pyroptosis.

Date of Award	2018
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology