A c sf1rb mutation uncouples two waves of microglia development in zebrafish

Development. 2021 Jan 11;148(1):dev194241. doi: 10.1242/dev.194241.

Abstract

In vertebrates, the ontogeny of microglia, the resident macrophages of the central nervous system, initiates early during development from primitive macrophages. Although murine embryonic microglia then persist through life, in zebrafish these cells are transient, as they are fully replaced by an adult population originating from larval hematopoietic stem cell (HSC)-derived progenitors. Colony-stimulating factor 1 receptor (Csf1r) is a fundamental regulator of microglia ontogeny in vertebrates, including zebrafish, which possess two paralogous genes: csf1ra and csf1rb Although previous work has shown that mutation in both genes completely abrogates microglia development, the specific contribution of each paralog remains largely unknown. Here, using a fate-mapping strategy to discriminate between the two microglial waves, we uncover non-overlapping roles for csf1ra and csf1rb in hematopoiesis, and identified csf1rb as an essential regulator of adult microglia development. Notably, we demonstrate that csf1rb positively regulates HSC-derived myelopoiesis, resulting in macrophage deficiency, including microglia, in adult mutant animals. Overall, this study contributes to new insights into evolutionary aspects of Csf1r signaling and provides an unprecedented framework for the functional dissection of embryonic versus adult microglia in vivo.

Keywords: Colony-stimulating factor 1 receptor; Hematopoiesis; Macrophages; Microglia; Zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Animals
  • Embryo, Nonmammalian / metabolism
  • Embryonic Development
  • Gene Expression Regulation, Developmental
  • Hematopoiesis
  • Hematopoietic Stem Cells / metabolism
  • Macrophages / metabolism
  • Microglia / metabolism*
  • Mutation / genetics*
  • Myeloid Cells / metabolism
  • Phagocytes / metabolism
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Zebrafish / embryology
  • Zebrafish / genetics*
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism

Substances

  • Zebrafish Proteins
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • csf1ra protein, zebrafish
  • csf1rb protein, zebrafish