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Review
, 144 (21), 3867-3878

Cortical Interneuron Development: A Tale of Time and Space

Affiliations
Review

Cortical Interneuron Development: A Tale of Time and Space

Jia Sheng Hu et al. Development.

Abstract

Cortical interneurons are a diverse group of neurons that project locally and are crucial for regulating information processing and flow throughout the cortex. Recent studies in mice have advanced our understanding of how these neurons are specified, migrate and mature. Here, we evaluate new findings that provide insights into the development of cortical interneurons and that shed light on when their fate is determined, on the influence that regional domains have on their development, and on the role that key transcription factors and other crucial regulatory genes play in these events. We focus on cortical interneurons that are derived from the medial ganglionic eminence, as most studies have examined this interneuron population. We also assess how these data inform our understanding of neuropsychiatric disease and discuss the potential role of cortical interneurons in cell-based therapies.

Keywords: Cell fate; Cortical interneurons; MGE; Parvalbumin; Somatostatin; Transcription factors.

Conflict of interest statement

Competing interestsJ.L.R. is cofounder, stockholder, and currently on the scientific board of Neurona, a company studying the potential therapeutic use of interneuron transplantation.

Figures

Fig. 1.
Fig. 1.
Cell fate specification models in the medial ganglionic eminence. A coronal section through a developing mouse brain at E12.5 (right). Within the brain, postmitotic neurons in the mantle zone are generated by two major progenitor zones: the ventricular (VZ) and subventricular zone (SVZ) (additional complexity exists, which we do not describe here). The VZ consists of neuroepithelial stem cells, called radial glia, which generate secondary progenitors of the non-epithelial SVZ. Three models can explain how progenitors in the MGE generate SST+ (yellow) or PV+ (blue) cortical interneurons (CINs). In model 1 (mosaic VZ model), early VZ progenitors are already committed to generate SST+ or PV+ CINs. In model 2 (homogenous VZ model), early VZ progenitors can generate both CIN subgroups (white), with the final decision taking place in the SVZ. In model 3 (direct versus indirect neurogenesis model), the SST+ subgroup is produced by direct neurogenesis from VZ progenitors, whereas PV+ CINs are produced by SVZ progenitors. CTX, neocortex; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; PV, parvalbumin; SST, somatostatin.
Fig. 2.
Fig. 2.
Spatial and temporal influences on cell fate specification in the MGE. (A) In the three models shown, different MGE regions along the dorsoventral or rostrocaudal axis (colored in the MGE VZ) bias MGE progenitors to generate one cell fate (thick arrows) over another (thin arrows). This bias can occur in each of the three cell specification models described in Fig. 1. The dorsal MGE (orange) biases the production of SST+ CINs (Flames et al., 2007; Fogarty et al., 2007; Sousa et al., 2009; Silberberg et al., 2016), whereas the ventral MGE (blue) biases the production of PV+ CINs (Flames et al., 2007; Inan et al., 2012; Silberberg et al., 2016). (B) Developmental time also biases MGE progenitors to generate more of one cell fate over another. Again, this bias can affect all three cell specification models. Early MGE progenitors from E11.5 give rise to mostly SST+ CINs (Hu et al., 2017), whereas later MGE progenitors from E14.5 give rise to mostly PV+ CINs (Xu et al., 2010; Hu et al., 2017). Abbreviations as Fig. 1.
Fig. 3.
Fig. 3.
Progenitor domains in the E12.5 mouse MGE. (A) Schema (left) depicting a lateral view of an E12.5 telencephalon and highlighting the locations of four coronal planes along the rostrocaudal axis. Nkx2-1 in situ hybridization (ISH) in these coronal sections from mouse E12.5 wild-type brain is shown (right). Red boxes denote corresponding locations magnified in B-D. (B-D) ISH for the indicated genes on a rostral to caudal series of coronal sections from mouse E12.5 wild-type brains. Each row comprises images of ISHs performed on adjacent sections of the same brain (B and C are also from the same brain). Sections within a column are from approximately the same level and plane of section. Red dashed lines delineate the VZ. Progenitor domain labels are based on terms used by Hu et al. (2017) and Flames et al. (2007). Black dotted lines delineate the proposed VZ domains derived from the combinatorial patterns of TF expression. Note that CoupTF2 is expressed in caudorostral and dorsoventral gradients (B,C), opposite to that of Otx2 (D). We identify (B,C) an MGE subdomain (rdMGEa, mdMGEa, MGE0) that is Nkx6-2+ CoupTF2+ Nkx2-1, which was not proposed by Flames et al. (2007). (E) Schema depicting the locations of the progenitor domains. CGE, caudal ganglionic eminence; cMGE, caudal medial ganglionic eminence; Ctx, neocortex; D, dorsal; EmT, eminentia thalami; GP, globus pallidus; L, lateral; LGE, lateral ganglionic eminence; M, medial; MGE, medial ganglionic eminence; mMGE, middle medial ganglionic eminence; mdMGE, middle dorsal medial ganglionic eminence; POA, preoptic area; POH, preoptic-hypothalamus; rdMGE, rostral dorsal medial ganglionic eminence; rvMGE, rostral ventral medial ganglionic eminence; Sep, septum; V, ventral. Scale bars: 1 mm in A; 500 µm in B.
Fig. 4.
Fig. 4.
Temporal specification in the MGE lineage. In this schematic, a mouse MGE VZ progenitor (white) undergoes a series of asymmetric divisions to generate V1, V2 and V3 progenitors, analogous to cell production in the invertebrate nerve cord (Kohwi and Doe, 2013). Each VZ division regenerates a VZ progenitor (white) and generates an SVZ progenitor (red). Each SVZ progenitor divides to produce a neuron and a sibling cell (which could be another SVZ progenitor, a neuron, a glia, or a dead cell). As shown here, the VZ progenitor 1 (VZ1) lineage generates a PV+ GP neuron (blue), the VZ2 lineage generates an SST+ CIN (yellow), and the VZ3 lineage generates a PV+ CIN (blue). In this model, CoupTF2 promotes the E12.5 VZ2 sublineage that gives rise to SST+ CINs, while inhibiting the E14.5 VZ3 sublineage that produces PV+ CINs (Hu et al., 2017). Sib, sibling daughter cell.
Fig. 5.
Fig. 5.
Loss-of-function mutants that influence the ratio of PV+/SST+ CINs. Multiple factors have been shown to influence the production, maturation and/or survival of CIN subgroups that express SST or PV. These include TFs, as well as cell signaling and membrane proteins. Yellow denotes factors that when lost result in a greater number of SST+ than PV+ CINs; blue denotes factors that when lost result in greater PV+ than SST+ CIN numbers. The loss of factors shown in red results in a relatively even loss of both CIN subgroups. Other factors, as shown in white, although expressed in these CINs and in progenitors, do not have a known function in establishing proper numbers of either subgroup.

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