Dystroglycan Suppresses Notch to Regulate Stem Cell Niche Structure and Function in the Developing Postnatal Subventricular Zone

Abstract

While the extracellular matrix (ECM) is known to regulate neural stem cell quiescence in the adult subventricular zone (SVZ), the function of ECM in the developing SVZ remains unknown. Here, we report that the ECM receptor dystroglycan regulates a unique developmental restructuring of ECM in the early postnatal SVZ. Dystroglycan is furthermore required for ependymal cell differentiation and assembly of niche pinwheel structures, at least in part by suppressing Notch activation in radial glial cells, which leads to the increased expression of MCI, Myb, and FoxJ1, transcriptional regulators necessary for acquisition of the multiciliated phenotype. Dystroglycan also regulates perinatal radial glial cell proliferation and transition into intermediate gliogenic progenitors, such that either acute or constitutive loss of function in dystroglycan results in increased oligodendrogenesis. These findings reveal a role for dystroglycan in orchestrating both the assembly and function of the SVZ neural stem cell niche.

MT1-MMP deficiency leads to defective ependymal cell maturation, impaired ciliogenesis, and hydrocephalus

“…With the maturation of ECs, the area of apical surface increases and acquires compacted cilia clusters that are initially scattered widely. The motile cilia are then clustered into an off-centered patch at the apical surface of ECs to facilitate coordinated ciliary beating (38,39). A correlation between defective ciliogenesis and disruption of planar polarity in ependymal motile cilia has been previously described (40).…”

Tissue mechanics regulate brain development, homeostasis and disease

“…For example, the binding of fibroblast growth factor 2 (FGF2), which is involved in NSC maintenance, to its receptor (FGF receptor) is facilitated by heparan sulfate proteoglycans (Rapraeger et al, 1994). In another recent example, the ECM receptor dystroglycan has been found to regulate ECM remodeling in the postnatal SVZ, and to regulate RGC proliferation and differentiation into gliogenic progenitors (McClenahan et al, 2016). The biophysical properties and innate stiffness of niches within the brain are also likely to play a role in cell fate.…”

Space Invaders

“…Laminin is further observed on the ventricular face of the V-SVZ at the center of ependymal pinwheels, where ependymal cells and NSCs contact each other. 70 Laminin signaling occurs via the interaction of dystroglycan on ependymal cells with integrin a6 on NSCs and is required for ependymal pinwheel formation and promotion of NSC interactions with blood vessels. 70,71 Integrin a6 expression is lost as NSCs differentiate.…”

“…70 Laminin signaling occurs via the interaction of dystroglycan on ependymal cells with integrin a6 on NSCs and is required for ependymal pinwheel formation and promotion of NSC interactions with blood vessels. 70,71 Integrin a6 expression is lost as NSCs differentiate. 71 Glioma cells with stem cell characteristics (enrichment of CD133, oligodendrocyte transcription factor, and Nestin) also express integrin a6.…”