Multipotency of Adult Hippocampal NSCs In Vivo Is Restricted by Drosha/NFIB

Abstract

SUMMARYMulti-lineage neuronal, astrocytic and oligodendrocytic potential is considered a neural stem cell (NSC) trait. However, hippocampal NSCs generate neurons and astrocytes but not oligodendrocytes in vivo and how this is regulated is unknown. Here we show that the RNAseIII Drosha is an intrinsic regulator of stem cell maintenance and differentiation in the adult mouse hippocampus. Inactivation of Drosha results in exhaustion of the NSC pool, premature arrest of neurogenesis, and induction of oligodendrocyte fate commitment. Drosha silences Nuclear Factor IB (NFIB) in hippocampal NSCs by targeting a double-stranded hairpin in the NFIB mRNA, thereby repressing its expression in a Dicer and miRNA-independent manner. We show that NFIB is required and sufficient for oligodendrocyte fate and knockdown of NFIB rescues neurogenesis by Drosha-deficient hippocampal NSCs. Our findings reveal a novel mechanism for stem cell maintenance and oligodendrocyte fate restriction in the adult hippocampus.3

The function of NFIX during developmental and adult neurogenesis

“…The NFI family has been extensively described in the developing brain, and have been implicated in multiple neurodevelopmental disorders (Malan et al, 2010), but how these factors function in the adult hippocampus is unclear. A recent study revealed a role for NFIB in promoting oligodendrogenesis within the adult SGZ (Rolando et al, 2016). Here, we present a contrasting role for NFIX within the adult hippocampus, revealing that NFIX drives a program of neuroblast differentiation and suppresses the latent potency of hippocampal precursor cells to generate…”

“…NFIX, and other NFIs are wellestablished regulators of astrocyte (Barry et al, 2008;Kang et al, 2012;Heng et al, 2014) and oligodendrocyte differentiation (Wong et al, 2007;Zhou et al, 2015;Rolando et al, 2016). Under physiological conditions, AH-NSCs generate astrocytes in addition to neurons (Bonaguidi et al, 2011).…”

“…Primary cultures of AH-NSCs also show limited capacity to generate oligodendrocytes, suggesting that barriers preventing the generation of oligodendrocytes from AH-NSCs are likely to be cell-intrinsic (Suh et al, 2007;Rolando et al, 2016). Recently, AH-NSCs were shown to be able to undergo a directed differentiation process to generate oligodendrocytes upon the forced expression of Olig2, Sox10 or Ascl1 using retroviruses (Braun et al, 2015).…”

“…Recently, AH-NSCs were shown to be able to undergo a directed differentiation process to generate oligodendrocytes upon the forced expression of Olig2, Sox10 or Ascl1 using retroviruses (Braun et al, 2015). Two studies followed this, where the removal of molecular blocks, either neurofibromin 1 (Sun et al, 2015) or Drosha (Rolando et al, 2016) were able to bias adult hippocampal precursors towards oligodendrocyte generation. The data in Chapter 5 adds Nfix to the short list of genes that function to inhibit oligodendrocyte formation within this population of progenitors.…”

“…The suggestion that AH-NSCs (Braun et al, 2015;Sun et al, 2015;Rolando et al, 2016) (Chapter 5) have the capacity to generate oligodendrocytes is an exciting development. The myelination of the hippocampus is often affected in disorders such as multiple sclerosis, Alzheimer's disease, bipolar disorder and in traumatic brain injury (Chambers and Perrone-Bizzozero, 2004;Meier et al, 2004;Noble, 2004;Geurts et al, 2007).…”