Autocrine Mfge8 Signaling Prevents Developmental Exhaustion of the Adult Neural Stem Cell Pool

Abstract

Adult neurogenesis, arising from quiescent radial-glia-like neural stem cells (RGLs), occurs throughout life in the dentate gyrus. How neural stem cells are maintained throughout development to sustain adult mammalian neurogenesis is not well understood. Here, we show that milk fat globule-epidermal growth factor (EGF) 8 (Mfge8), a known phagocytosis factor, is highly enriched in quiescent RGLs in the dentate gyrus. Mfge8-null mice exhibit decreased adult dentate neurogenesis, and furthermore, adult RGL-specific deletion of Mfge8 leads to RGL overactivation and depletion. Similarly, loss of Mfge8 promotes RGL activation in the early postnatal dentate gyrus, resulting in a decreased number of label-retaining RGLs in adulthood. Mechanistically, loss of Mfge8 elevates mTOR1 signaling in RGLs, inhibition of which by rapamycin returns RGLs to quiescence. Together, our study identifies a neural-stem-cell-enriched niche factor that maintains quiescence and prevents developmental exhaustion of neural stem cells to sustain continuous neurogenesis in the adult mammalian brain.

Loss of postnatal quiescence of neural stem cells through mTOR activation upon genetic removal of cysteine string protein-α

“…S5), another feature previously known to occur upon mTOR hyperactivation as a consequence of the deletion of disrupted-in-schizophrenia 1 (DISC1) (49,50). A very recent study has shown that autocrine signaling mediated by milk fat globule-EGF 8 (Mfge8) prevents developmental exhaustion of the adult neural stem cell pool (51). Remarkably, loss of Mfge8 promotes activation of RGLs and mTOR1 signaling that become rescued by rapamycin-mediated inhibition (51).…”

“…A very recent study has shown that autocrine signaling mediated by milk fat globule-EGF 8 (Mfge8) prevents developmental exhaustion of the adult neural stem cell pool (51). Remarkably, loss of Mfge8 promotes activation of RGLs and mTOR1 signaling that become rescued by rapamycin-mediated inhibition (51). Given the striking similarity of phenotypes related to mTOR hyperactivation in mice lacking CSP-α and mice lacking Mfge8, it would not be surprising that CSP-α could play a role within the signaling pathway mediated by this niche factor.…”

Apical progenitors remain multipotent throughout cortical neurogenesis

“…Both of these genes thus act on the dynamically regulated balance between self-renewal and differentiation during corticogenesis (Paridaen and Huttner, 2014). Repressed, normally late-onset, genes included Tenascin c ( Tnc ), an extracellular glycoprotein involved in the onset of gliogenesis late in corticogenesis (Garcion et al, 2004) and Mfge8 , coding for an EGF-like domain containing protein, which regulates quiescence in adult neural stem cells (Zhou et al, 2018). Together, these results reveal that the temporal shift in the neurogenic competence of AP 15→12 is accompanied by a corresponding wholesale shift in their global molecular identity.…”

Defining the adult hippocampal neural stem cell secretome: in vivo versus in vitro transcriptomic differences and their correlation to secreted protein levels

“…In addition to creating mature cell types, NSCs also secrete an array of growth factors and cytokines, collectively termed the stem cell secretome (Drago et al 2013). In the healthy adult SGZ, NSCs and their progenitors (together NSPCs) have been shown to produce the secreted factors milk-fat globule EGF-factor 8 (MFGE8) and vascular endothelial growth factor (VEGF), both of which regulate NSPC maintenance through autocrine signaling (Kirby et al 2015;Zhou et al 2018), as well as PTN which drives maturation of immature, developing neurons (Tang et al 2019). However, while the secretome of other tissue stem cells, such as mesenchymal stem cells, has been extensively catalogued (Liang et al 2014), a comprehensive characterization of the NSPC secretome is lacking (Andres et al 2011;Ryu et al 2004;Yasuhara et al 2006;Ourednik et al 2002;Tang et al 2019).…”