Abstract
Diverse γ-aminobutyric acid (GABA)-ergic interneurons provide different modes of inhibition to support circuit operation in the neocortex. However, the cellular and molecular mechanisms underlying the systematic generation of assorted neocortical interneurons remain largely unclear. Here we show that NKX2.1-expressing radial glial progenitors (RGPs) in the mouse embryonic ventral telencephalon divide progressively to generate distinct groups of interneurons, which occupy the neocortex in a time-dependent, early inside-out and late outside-in, manner. Notably, the late-born chandelier cells, one of the morphologically and physiologically highly distinguishable GABAergic interneurons, arise reliably from continuously dividing RGPs that produce non-chandelier cells initially. Selective removal of Partition defective 3, an evolutionarily conserved cell polarity protein, impairs RGP asymmetric cell division, resulting in premature depletion of RGPs towards the late embryonic stages and a consequent loss of chandelier cells. These results suggest that consecutive asymmetric divisions of multipotent RGPs generate diverse neocortical interneurons in a progressive manner.
Highlights
Diverse γ-aminobutyric acid (GABA)-ergic interneurons provide different modes of inhibition to support circuit operation in the neocortex
The same amount of RCAS-enhanced green fluorescent protein (EGFP) retrovirus was injected at each embryonic stage, and numerous radial glial progenitors (RGPs) were selectively infected and thereby labeled in the ventricular zone (VZ) of the medial ganglionic eminence (MGE)/preoptic area (PoA), but not the lateral ganglionic eminence (LGE) or the neocortex (NCX) (Supplementary Fig. 2c)
This strategy is more accurate for examining the temporal neocortical interneuron output of dividing MGE/PoA RGPs than the typical inducible genetic fate mapping approach using Nkx2.1-CreER;Ai9-tdTomato mice, in which labeled interneurons arise from both dividing and non-dividing RGPs, as well as intermediate progenitors (IPs) in the subventricular zone (SVZ) at the time of tamoxifen (TM) induction as NKX2.1 is expressed in MGE/PoA RGPs and IPs regardless of cell cycle phase at the embryonic stage[22,23,38,39]
Summary
Diverse γ-aminobutyric acid (GABA)-ergic interneurons provide different modes of inhibition to support circuit operation in the neocortex. Derived from neuroepithelial cells, radial glial cells in the developing dorsal telencephalon account for the major neural progenitor cells that generate virtually all neocortical excitatory neurons[5,6,7] They reside in the ventricular zone (VZ) with a characteristic bipolar morphology and actively divide at the luminal surface of the VZ. One mechanism involves a common pool of progenitors that continuously undergoes asymmetric neurogenesis and becomes progressively fate-restricted over time, thereby generating distinct neuronal subtypes at different times. This is the case for the principal neuronal types found in the vertebrate retina[8,9,10]. The other mechanism is via multiple pools of fate-restricted progenitors that may be spatially, temporally, or molecularly segregated so as to produce distinct neuronal types, such as the developing spinal cord, where different populations of neurons arise from progenitors expressing distinct transcription factors[11]
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