LRP2 in ependymal cells regulates BMP signaling in the adult neurogenic niche

Abstract

SummaryThe microenvironment of growth factors in the subependymal zone (SEZ) of the adult brain provides the instructive milieu for neurogenesis to proceed in this germinal niche. In particular, tight regulation of bone morphogenetic protein (BMP) signaling is essential to balance proliferative and non-proliferative cell fate specification. However, the regulatory pathways that control BMP signaling in the SEZ are still poorly defined. We demonstrate that LRP2, a clearance receptor for BMP4 is specifically expressed in ependymal cells of the lateral ventricles in the adult brain. Intriguingly, expression is restricted to the ependyma that faces the stem cell niche. Expression is not seen in ependyma elsewhere in the lateral ventricles or in the dentate gyrus, the second major neurogenic zone of the adult brain. We further show that lack of LRP2 expression in adult mice results in impaired proliferation of neural precursor cells in the SEZ resulting in decreased numbers of neuroblasts reaching the olfactory bulb. Reduced neurogenesis coincides with increased BMP4 expression and enhanced activation of downstream mediators phospho-SMAD1/5/8 and ID3 in the stem cell niche. Our findings suggest a novel mechanism whereby LRP2-mediated catabolism of BMP4 in the ependyma modulates the microenvironment of the SEZ and enables adult neurogenesis to proceed.

LRP2 Acts as SHH Clearance Receptor to Protect the Retinal Margin from Mitogenic Stimuli

“…We explored a role for LRP2 in the functional integrity of the mammalian eye, a process disturbed by receptor deficiency in humans and mice (Gajera et al, 2010;Pober et al, 2009;Storm et al, 2014). We carried out our analyses using two different Lrp2 null alleles that disrupt LRP2 synthesis in mice.…”

“…For analysis of postnatal and adult stages, Lrp2 +/À animals were crossed with the ENU line 267 that carries a premature stop codon in the sequence encoding the extracellular domain of LRP2 (Lrp2 267/+ ) (Zarbalis et al, 2004). Compound heterozygous mice (Lrp2 267/À ) exhibit a higher rate of perinatal survival compared to Lrp2 À/À animals due to the (FVB/NJ 3 C57BL/6J) background of line 267 (Gajera et al, 2010). For both alleles, LRP2-deficient animals (Lrp2 À/À or Lrp2 267/À ) were compared to their respective heterozygous or wild-type littermates (jointly referred to as controls).…”

“…Our choice was guided by large eye phenotypes seen in LRP2-deficient humans (Pober et al, 2009) and mouse and zebrafish models (Gajera et al, 2010;Veth et al, 2011). Yet, the mechanism of LRP2 action during eye development and whether it functions as SHH binding protein in this context remained unclear.…”

In Vitro Models for Neurogenesis

“…Ependymal cells not only act as a physical barrier to protect the niche from noxious substances in the CSF, they serve as a sensor of CSF components through coupling with SVZ astrocytes, and secrete proneurogenic factors, such as noggin to create a favorable neurogenic environment (Lim et al 2000). The apical region of the ependymal cells facing the neurogenic regions of the SVZ, but not the SGZ, express low-density lipoprotein-related protein 2 (LRP2) that negatively modulate BMP signaling to ensure cell proliferation and neurogenesis (Gajera et al 2010). Some of the type B cells have long processes intercalating between adjacent ependymal cells to access the ventricular area (Silva-Vargas et al 2013;Codega et al 2014).…”

Inducible expression of noggin selectively expands neural progenitors in the adult SVZ

“…BMP signaling plays multiple key roles in CNS morphogenesis from neural induction to patterning of the nervous system, proliferation and lineage differentiation (Chen and Panchision, 2007;Bond et al, 2012). Since the effects of BMP signaling appear to depend on signal strength, inhibitors such as noggin may be critically required in modulating signaling by pathway members (e.g., Bonaguidi et al, 2008;Colak et al, 2008;Gajera et al, 2010;Mira et al, 2010). In the adult SVZ BMP signaling is active as indicated by the phosphorylation of SMAD1/5/8 (Colak et al, 2008); transit amplifying cells (C cells), activated astrocytes (B cells), and endothelial cells (Mathieu et al, 2008) express BMPs, while noggin is produced by ependymal and B cells (Lim et al, 2000;Peretto et al, 2004).…”