Abstract
Microglia are the primary immune cells in the central nervous system, which plays a vital role in neuron development and neurodegenerative diseases. Microglial precursors in peripheral hematopoietic tissues colonize the central nervous system during early embryogenesis. However, how intrinsic and extrinsic signals integrate to regulate microglia’s differentiation remains undefined. In this study, we identified the cerebral white matter hyperintensities susceptibility gene, programmed cell death protein 11 (PDCD11), as an essential factor regulating microglia differentiation. In zebrafish, pdcd11 deficiency prevents the differentiation of the precursors to mature brain microglia. Although, the inflammatory featured macrophage brain colonization is augmented. At 22 h post fertilization, the Pdcd11-positive cells on the yolk sac are distinct from macrophages and neutrophils. Mechanistically, PDCD11 exerts its physiological role by differentially regulating the functions of nuclear factor-kappa B family members, P65 and c-Rel, suppressing P65-mediated expression of inflammatory cytokines, such as tnfα, and enhancing the c-Rel-dependent appearance of tgfβ1. The present study provides novel insights in understanding microglia differentiation during zebrafish development.
Highlights
Cerebral white matter hyperintensities (WMH), known as leukoaraiosis, are common in the aging population and areThese authors contributed : Ruimeng Yang, Ming ZhanEdited by M
By whole-mount in situ hybridization (WISH), we found that aside from the obvious expression signal in the neuron epithelium, scattered cells on the yolk sac (YS) were detected from 7-somite stages (Fig. 6a)
Myeloid progenitor cells expressing Pu.1 emerged within the anterior lateral plate mesoderm (ALPM) at the 5-ss and migrated into the rostral blood island (RBI) and onto the YS
Summary
Cerebral white matter hyperintensities (WMH), known as leukoaraiosis, are common in the aging population and are. The innate immune cells of the central nervous system (CNS), enter the brain during early embryogenesis and play important roles in white matter pathology [8]. As influenced by their environment, microglia assume different molecular patterns ranging from M1 phenotype in secretion pro-inflammatory cytokines to M2 phenotype in inflammation resolution and tissue repair [9]. Transforming growth factor-beta (TGF-β) family members are cytokine important for both innate and adaptive immune functions [14] It is required for the maintenance of the microglia-specific homeostatic gene signature. This imbalanced macrophage generation, likely caused by uncontrolled P65 activation, causes inflammatory gene upregulation and suppresses c-Rel-dependent Tgfβ expression under pdcd deficiency
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