Myh9 Plays an Essential Role in the Survival and Maintenance of Hematopoietic Stem/Progenitor Cells

Abstract

<i>Myosin heavy chain 9</i> (<i>MYH9</i>) gene encodes a protein named non-muscle heavy chain IIA (NMHC IIA), interacting with actin and participating in various biological processes. Mutations in <i>MYH9</i> cause an array of autosomal dominant disorders, known as <i>MYH9</i>-related diseases (<i>MYH9</i>-RD). However, the role of <i>MYH9</i> in normal hematopoiesis remains largely unexplored. By using <i>Mx1-cre Myh9</i> conditional knockout mice, we established an inducible system to precisely inactivate <i>Myh9</i> function in hematopoietic cells in vivo. The results showed that deletion of <i>Myh9</i> led to severe defects in hematopoiesis, characterized by pancytopenia, drastic decreases of hematopoietic stem/progenitor cells (HSPC), and bone marrow failure, causing early lethality in mice. The defect in hematopoiesis caused by <i>Myh9</i> ablation is cell autonomous. In addition, <i>Myh9</i> deletion impairs HSPC repopulation capacity and increases apoptosis. RNA sequencing results revealed significant alterations in the expression of genes related to HSC self-renewal and maintenance, while multiple signal pathways were also involved, including genes for HSC and myeloid cell development, intrinsic apoptosis, targets of mTOR signaling, and maturity of hematopoietic cells. Our present study suggests an essential role for <i>Myh9</i> in the survival and maintenance of HSPC in normal hematopoiesis.