Neurogenesis From Embryo to Adult - Lessons From Flies and Mice

Abstract

The human brain is composed of billions of cells, including neurons and glia, with an undetermined number of subtypes. During the embryonic and early postnatal stages, the vast majority of these cells are generated from neural progenitors and stem cells located in all regions of the neural tube. A smaller number of neurons will continue to be generated throughout our lives, in localized neurogenic zones, mainly confined at least in rodents to the subependymal zone of the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus. During neurogenesis, a combination of extrinsic cues interacting with temporal and regional intrinsic programs are thought to be critical for increasing neuronal diversity, but their underlying mechanisms need further elucidation. In this review, we discuss the recent findings in Drosophila and mammals on the types of cell division and cell interactions used by neural progenitors and stem cells to sustain neurogenesis, and how they are influenced by glia.

Keywords: adult neurogenesis; extrinsic factors; glia; intrinsic factors; neural progenitors; neural stem cells; neurogenesis; niche.

FIGURE 1

Embryonic, larval and adult neurogenesis in flies and mammals. (A) Overview of embryonic mammalian neurogenesis in the neocortex and olfactory bulb. In the developing dorsal pallium, the nervous system originates from neuroepithelial cells (NECs) that initially proliferate symmetrically before they transition to apical radial glial cells (aRG). aRGs give rise to neurons directly (blue), or indirectly (green) through intermediate neural progenitors (INP). Direct neurogenesis predominates in the olfactory bulb (OB, blue); indirect neurogenesis predominates in the neocortex (Ncx, green). (B) Adult mammalian neurogenesis in the subgranular zone (SGZ, yellow) and subependymal zone (SEZ, red). Quiescent postnatal neural stem cells in the SGZ (SGZ NSC) (yellow) undergo symmetric self-renewal before they give rise to transient amplifying cells, a type of intermediate neural progenitor (INP/TAP) (green) and differentiate into dentate gyrus granule neurons. Quiescent embryonic SEZ NSCs (red) are activated in the adult stage and undergo either symmetric self-renewing divisions (20%) or primarily produce INP/TAPs before differentiating into OB interneurons. (C) Different modes of division of neural progenitors in embryonic Drosophila. In the embryo, the nervous system originates from a neuroectoderm before they transit into neuroblasts (Nbs). Type 0 Nbs (blue) self-renew and produce a single ventral nerve cord (VNC) neuron at each division. Type I Nbs (yellow) self-renew and produce ganglion mother cells (GMC) that divide once to generate two cells in the central brain (CB, yellow) and VNC (yellow). Type II Nbs (orange) self-renew and produce intermediate neural progenitors (INP), which also self-renew multiple times before producing GMCs, which divide once and differentiate into central brain neurons (orange). Optic lobe cells (OL, green) originate from NECs. (D) Different modes of division of neural progenitors in the Drosophila larval brain. After the first, embryonic, wave of neurogenesis (shown in C), most of the remaining central brain and ventral nerve cord neuroblasts, and optic lobe NECs enter a quiescent state (dashed lines). In a second, larval, wave of neurogenesis, via ganglion mother cells (GMC), Type I Nbs in the central brain (CB, yellow region depicted in the larval brain) produce the majority of adult central brain cells, and Type II Nbs (orange region) produce the vast majority of central complex cells, an essential central brain region for sensorimotor integration (Pfeiffer and Homberg, 2014). Quiescent outer proliferation center (OPC) NECs are activated to transition into Type I Nbs (green region) and produce medulla cells in the OL. Type III Nbs (red) originate from NECs of the inner proliferation center (IPC), and undergo symmetric self-renewal to produce two identical progenies that retain the identity of neuroblasts and produce lobula plate cells in the OL.

FIGURE 2

Neural stem cell niches in the Drosophila larval medulla and adult mouse hippocampus. (A,A’) Neural stem cell niche in the larval medulla: (A) neuroepithelial cells (NECs, DE-Cadherin, red) in the outer proliferation center, and their transition into medulla neuroblasts (Nbs, Miranda, green), ganglion mother cells (GMCs, Prospero, blue) and medulla postmitotic cells (DAPI, gray). Arrows indicate transition direction. Scale bar = 20 μm. (B,B’) Neural stem cell niche in the adult mouse hippocampus: (B) Neural stem cells with radial glia-like morphology (pink) are located in the hippocampal dentate gyrus (GFAP, white; DAPI, blue). Their soma sits at the border of the densely packed granule cell layer (GCL), the so-called subgranular zone (SGZ). Their primary process extends across the GCL and reaches the inner molecular layer (ML). NSCs express the markers Sox2, Prominin 1, Nestin (not shown) and glial fibrillary acidic protein GFAP (white), among others, and are mostly quiescent. Surrounding the NSCs a variety of highly branched niche astrocytes located in different layers are found. Those in the ML, GCL, and hilus are shown in green, red, and yellow, respectively. Mature astrocytes do not proliferate and express markers such as glial glutamate transporter 1 (GLT1), S100β (not shown) and GFAP (white), among others. Other niche elements such as blood vessels, INPs and neurons are not shown. (B’) GFAP immunostaining, marking both NSCs and astrocytes with distinctive morphologies.

FIGURE 3

Temporal patterning in neural progenitors in Drosophila and in mammals. Upper panel, transcription factor sequences expressed in embryonic and larval Drosophila neural progenitors. Lower panel, core transcription factor sequence expressed in glutamatergic neurogenesis in the developing cerebral cortex, adult SGZ neurogenesis and adult OB glutamatergic juxtaglomerular interneuron neurogenesis. aRG, apical radial glia; c-OPC, central outer proliferation center; d-IPC, distal inner proliferation center; INP, intermediate neural progenitors; Nbs, neuroblasts; t-OPC, tip of the outer proliferation center; VNC, ventral nerve cord.

FIGURE 4

Spatial and temporal patterning on NSCs act together to promote neural diversity in the central nervous system.

FIGURE 5

Niche glia-derived signals in the larval Drosophila brain and adult neurogenic areas. (A) Schematic representation of niche glia-derived signals in the larval central brain (CB, yellow) and optic lobe (OL, green), and schematic illustration of a GFP-labeled cortex glia Flp-out clone (gray) showing how the cortex glia ensheaths a Type I Nb (blue), ganglion mother cells (orange) and its neural progeny (yellow) in the central brain. (B) Schematic representation of niche astroglia-derived signals in the adult neurogenic areas. Astrocytes (blue cells) are regionally specified and secrete a variety of local signals to regulate neurogenesis. Astrocytes from the SEZ (the site of neuronal birth) secrete Wnt7a while olfactory bulb astrocytes (OB, the site of neuronal integration) express the Wnt antagonist sFRP4. Hippocampal astrocytes specifically release Wnt3, IL-1β, IL-6, and neurogenesin-1. Rostral migratory stream (RMS) astrocytes that ensheath migratory neuroblasts en route to the OB and hippocampal astrocytes also modulate adult neurogenesis through the supply of neurotransmitters (glutamate, D-serine).