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Review
. 2018 Oct 12;362(6411):176-180.
doi: 10.1126/science.aas9435.

Neuronal specification in space and time

Isabel Holguera  1 , Claude Desplan  2   3
Affiliations
Review

Neuronal specification in space and time

Isabel Holguera et al. Science. .

Abstract

To understand how neurons assemble to form functional circuits, it is necessary to obtain a detailed knowledge of their diversity and to define the developmental specification programs that give rise to this diversity. Invertebrates and vertebrates appear to share common developmental principles of neuronal specification in which cascades of transcription factors temporally pattern progenitors, while spatial cues modify the outcomes of this temporal patterning. Here, we highlight these conserved mechanisms and describe how they are used in distinct neural structures. We present the questions that remain for a better understanding of neuronal specification. Single-cell RNA profiling approaches will potentially shed light on these questions, allowing not only the characterization of neuronal diversity in adult brains, but also the investigation of the developmental trajectories leading to the generation and maintenance of this diversity.

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Figures

Fig.1:
Fig.1:. Modes of division of neural progenitors. A. Neurogenesis in the primate cortex.
aRG undergo symmetric cell divisions to expand their pool (proliferative phase), and then transit to a neurogenic phase where they generate neurons directly or indirectly through intermediate progenitors such as bIPs and oRGs. Changes in TF expression in progenitors over time are shown as changes in cell color. aRG: apical radial glia. bIP: basal intermediate progenitor. oRG: outer radial glia. GW: gestational week. B. Different modes of NB division in Drosophila. Type 0 NBs self-renew and generate a single neuron at each division. Type I NBs self-renew and produce GMCs that divide once to produce one NotchON and one NotchOFF neuron. Type II NBs have an increased neuronal output by generating INPs, which themselves asymmetrically divide multiple times to produce GMCs. Both NBs and INPs sequentially express series of tTFs as they age (examples of these and additional temporal factors in NBs are shown). Cas: Castor. D: Dichaete. Svp: Seven-up. Imp: IGF-II mRNA-binding protein. Chinmo: Chronologically inappropriate morphogenesis. Syp: Syncrip. EcR: ecdysone receptor. Br: Broad. E93: Eip93. Grh: Grainy head. Ey: Eyeless. hALH: hours after larval hatching. Modified after Doe et al., 2017 (3).
Fig.2:
Fig.2:. Temporal patterning of progenitors. A. Multipotent progenitor model of neurogenesis in the mammalian cortex. Upper panel:
Asymmetric MADM clone showing the progeny of a single aRG that span each layer (II–VI) of the mouse cortex (Picture from S. Hippenmeyer (7)). Bottom panel: A common progenitor generates neurons for the different cortical layers (VI through II) sequentially in an inside-out fashion. Ikaros (Ikzf1) is an example of a TF specifying deep layer neuronal identity. Changes in TF expression in progenitors over time are shown with color changes. aRG: apical radial glia. IP: intermediate progenitor. VZ: ventricular zone. SVZ: subventricular zone. CP: cortical plate. E: embryonic day. B. Temporal patterning in Drosophila optic lobe NBs. Upper panel: Sequential expression of tTFs in Drosophila type I optic lobe NBs, specifying distinct neuronal (e.g. Mi1, Tm1, Tm3, Tm5) and glial identities in each temporal window. Cross-regulatory interactions between tTFs are shown. Bottom panel: Newly born neurons displace older siblings away from the parent NB, generating a birth order-dependent layered neuronal arrangement in the medulla cortex in third instar larvae (L3). C. Vertebrate retina. RPCs sequentially generate the seven retinal cell types in overlapping waves. The TF Ikzf1 specifies early-born fates while Casz1 specifies late born fates. RPC: retinal progenitor cell. RGC: retinal ganglion cell. HC: horizontal cell. AC: amacrine cell. C: cone. R: rod. BP: bipolar cell. MG: Müller glia. E: embryonic day. P: postnatal day.
Fig. 3.:
Fig. 3.:. Spatial patterning of progenitors. A. Integration between spatial and temporal patterning in the Drosophila optic lobe. Left panel:
Regionalization of the Drosophila optic lobe neuroepithelium (NE) by the expression of the TFs Optix, Vsx and Rx. Middle panel: Sequential expression of the tTFs Hth-Ey-Slp-D in optic lobe NBs of different ages. Right panel: Schematic of spatial and temporal factors acting in optic lobe NBs. The neuroepithelium is additionally patterned by the signaling molecules Dpp and Wg and by Hh in the ventral part, creating eight compartments along the dorsoventral axis. B. Morphogens spatially pattern the mammalian spinal cord and telencephalon. Left panel: Dorso-ventral patterning of the neural tube by Wnt/BMP and Shh that regulate the expression of TFs in progenitors, which produce different types of neurons. Early born neurons are different from those produced at later stages. The progenitor domains and the neurons generated in each one of them are indicated. NC: notochord. FP: floor plate. RF: roof plate. VZ: ventricular zone. MZ: mantle zone. Right panel: Schematic of the mouse embryonic telencephalon that is similarly patterned by the morphogens Wnt and BMPs from the dorsal hem and ventrally by the secretion of Shh. FGFs are secreted from a rostral signaling center (violet). GABAergic interneurons are generated from the lateral (LGE) and medial ganglionic eminences (MGE) in the ventral telencephalon and migrate tangentially to reach the cortex.
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