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

Septins in Stem Cells

“…A main unsolved question remains the nature of the role of the Septin network and thus filaments in HSCs and even in yeast. While the function of Septins has been frequently linked to their function within the filament network, recent data from our laboratory imply a non-filament linked, distinct polar/apolar distribution of Sept7, Sept2 and Sept6 in HSCs ( Kandi et al, 2021b ). For example, the distribution of Sept7 and Sept2 in HSCs is quite distinct ( Figure 1C ), which questions whether these Septins are indeed strongly interacting.…”

“…In addition, the extent of this symmetry correlates with the age of the HSCs. With respect to the distribution of Septins within HSCs, recent published data show that both spots and blobs of certain Septins (Sept7, Sept6, Sept2) are found within HSCs ( Senger et al, 2017 ; Kandi et al, 2021b , see Table1 ). The distinct roles of these specific structures (spots, blobs) remain elusive.…”

Septins as membrane influencers: direct play or in association with other cytoskeleton partners

“…Cdc42-regulated BORG family known to regulate the septin network (Joberty et al, 2001), compartmentalizes polarity proteins when complexed with SEPT7 (Kandi et al, 2021).…”