Persistent Expression of VCAM1 in Radial Glial Cells Is Required for the Embryonic Origin of Postnatal Neural Stem Cells

Abstract

During development, neural stem cells (NSCs) undergo transitions from neuroepithelial cells to radial glial cells (RGCs), and later, a subpopulation of slowly dividing RGCs gives rise to the quiescent adult NSCs that populate the ventricular-subventricular zone (V-SVZ). Here we show that VCAM1, a transmembrane protein previously found in quiescent adult NSCs, is expressed by a subpopulation of embryonic RGCs, in a temporal and region-specific manner. Loss of VCAM1 reduced the number of active embryonic RGCs by stimulating their premature neuronal differentiation while preventing quiescence in the slowly dividing RGCs. This in turn diminished the embryonic origin of postnatal NSCs, resulting in loss of adult NSCs and defective V-SVZ regeneration. VCAM1 affects the NSC fate by signaling through its intracellular domain to regulate β-catenin signaling in a context-dependent manner. Our findings provide new insight on how stem cells in the embryo are preserved to meet the need for growth and regeneration.

Development of Ependymal and Postnatal Neural Stem Cells and Their Origin from a Common Embryonic Progenitor

“…We analyzed the molecular marker expression and apical surface sizes of 153–888 ventricular epithelial cells per time point (Figure 2A). In agreement with previous findings, we found that VCAM1 was expressed in the apical domain of many embryonic VZ cells (Figure 2A; Hu et al, 2017). During postnatal development, VCAM1 expression decreased in cells that continued to expand their apical domains (Figures 2A–2C).…”

“…E1 cells also adhere to B1 cells in pinwheel cores. VCAM1 has been shown to be expressed on the apical domain of quiescent B1 cells (Kokovay et al, 2012; Codega et al, 2014; Hu et al, 2017), and blocking antibodies against VCAM1 destabilize junctional complexes and disrupt epithelial cytoarchitecture, resulting in a loss of pinwheels (Kokovay et al, 2012). However, the time at which VCAM1 function is necessary for the development of pinwheels, and the potential involvement of other adhesion molecules expressed by E1 cells, B1 cells, or both are not well understood.…”

“…We found that expression of VCAM1, which is expressed by most RG cells by E17.5, preceded the onset of RG apical domain expansion that occurred between P0 and P5 (Figures 2A and 2D–2F). Recent work has also demonstrated that widespread VCAM1 expression in RG cells at birth is progressively lost by epithelial cells with large apical domains, likely corresponding to differentiating and maturing E1 cells (Huetal.,2017). Interestingly, VCAM1 expression persists during E1 cell differentiation for a short period (Figures 2B and 2C).…”

“…The apical domains of B1 cells share the surface of the ventricular wall with E1 cells. Both cell types are organized into polarized structures called pin-wheels, where the small apical endings of B1 cells form the center of pinwheels and are surrounded by a rosette of ependymal cells with large apical surfaces (Mirzadeh et al, 2008; Kokovay et al, 2012; Hu et al, 2017). This organization is unique to regions of the ventricular walls where neurogenesis continues throughout adulthood.…”

Akhirin regulates the proliferation and differentiation of neural stem cells/progenitor cells at neurogenic niches in mouse brain

“…To investigate whether reduced cell proliferation causes decreased pool of NSCs/NPCs, we performed IHC at both WT and AKH −/− SVZ niche with vascular cell adhesion molecule‐1 (Vcam1) (Figure a,a',e,e') that is involved in maintaining the quiescent state of NSCs to avoid premature neuronal differentiation (Hu et al, ; Kokovay et al, ). We also performed IHC with mammalian achaete‐scute homolog‐1 (Mash1) (Figure b,b',f,f') that plays dual role, where its oscillatory expression mode is involved in maintaining the proliferation of NPCs, while sustained expression mode promotes differentiation into neuronal lineages (Tang, ).…”