A Cdc42-Borg4-Septin 7 axis regulates HSCs polarity and function

Abstract

Aging of hematopoietic stem cells (HSCs) is caused by an elevated activity of the small RhoGTPase Cdc42 and an apolar distribution of proteins. Mechanisms by which Cdc42 activity controls polarity of HSCs are not known. Binder of RhoGTPases proteins (borgs) are known effector proteins of Cdc42 that are able to regulate the cytoskeletal septin network. Here we show that Cdc42 interacts with borg4, which in turn interacts with septin 7 to regulate the polar distribution of Cdc42, borg4 and septin 7 within HSCs. Genetic deletion of either borg4 or septin 7 in HSCs resulted in a reduced frequency of HSCs polar for Cdc42 or borg4 or septin 7 and a reduced engraftment potential and decreased lymphoid-primed multipotent progenitors (LMPPs) frequency in the bone marrow. In aggregation our data identify a Cdc42-borg4-septin 7 axis to be essential for maintenance of polarity within HSCs and for HSC function and provide rationale for further investigating the role of borgs and septins for the regulation of compartmentalization within stem cells. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/435817v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@168dd5org.highwire.dtl.DTLVardef@b9b4a3org.highwire.dtl.DTLVardef@26e05org.highwire.dtl.DTLVardef@1851fcf_HPS_FORMAT_FIGEXP M_FIG C_FIG