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Multipotent radial glia sequentially deploy fate-restricted intermediate progenitors to diversify cortical interneurons

Sean M. KellyiD, Ricardo RaudalesiD, Monika MoissidisiD, Z. Josh HuangiD

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Abstract

GABAergic interneurons deploy numerous inhibitory mechanisms that regulate cortical circuit operation, but the developmental programs that generate diverse interneuron types are not yet well understood. We carried out a comprehensive genetic fate mapping of the radial glial progenitors (RGs) and intermediate progenitors (IP) in the medial ganglionic eminence (MGE) in mice. We reveal that Nkx2.1+ RGs are multipotent and mediate two consecutive waves of neurogenesis, each sequentially generating different sets of interneuron types that laminate the neocortex in an inside-out-inside order. The first wave begins early and is restricted to the caudal MGE, has limited neurogenic window and capacity, and involves mostly apical IPs. The second wave begins later throughout the MGE, has an extended time course and large neurogenic capacity, and features a large set of fate-restricted basal IPs that amplify and diversify interneurons. Chandelier cells are generated toward the end of each wave and laminate in an outside-in order. Therefore, separate pools of multipotent RGs deploy temporal cohorts of IPs to sequentially generate diverse interneuron types.

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Claude Opus 5.5 · xhigh effort · 8 Nov 2026 · from the full text of version 2 (21 Sept 2026) · CC BY 4.0

Fate mapping in mouse shows two separate MGE radial glia pools; the later pool uses temporal cohorts of fate-restricted basal intermediate progenitors to amplify and diversify cortical interneurons.

The paper says a cellular-resolution lineage framework linking MGE progenitor types to interneuron types was missing, and that the role of intermediate progenitors was largely unexplored. It combines intersectional recombinase drivers to fate-map radial glia and intermediate progenitors across neurogenesis and to birthdate their progeny.

Key results

  1. ShownThe MGE contains two radial glia pools. Early ones (RGE, labeled at E10) stay in the caudal MGE and yield few interneurons, mostly infragranular. Later ones (RGL, labeled at E12) span the whole MGE and yield abundant interneurons in L2-L6.

    E10 labeling gave sparse P28 progeny, mostly L5 with no L4 labeling, reproducible across more than 10 litters. E12 labeling gave abundant L2-6 progeny. Output was quantified with n = 6 sections from 3 brains per time point. · The MGE comprises two separate RG pools with…; Figure legends

  2. ShownBoth RGE and RGL are multipotent. Their progeny settle in the cortex in an inside-out-inside sequence, shown by EdU/BrdU birthdating combined with fate mapping.

    For RGE, E11 EdU marked fate-mapped L6 but not L2/3 cells, while E13 BrdU marked L2/3 and L5 cells. For RGL, E16 EdU marked mostly supragranular cells, while E18 BrdU marked a significant number of L5/6 cells. EdU+/BrdU+ double-labeled cells were also found. · RGEs and RGLs are multipotent and generate…; Figure legends

  3. ShownIntermediate progenitors form temporal cohorts with restricted laminar fate. Early Ascl1+ apical IPs yield sparse output; from E12, basal IPs yield abundant cells with sharper laminar restriction than Nkx2.1 mapping. Ascl1 bIPs follow inside-out-inside; Dlx1 bIPs follow inside-out and lack the last deep-layer set.

    Ascl1-CreER or Dlx1-CreER intersected with Nkx2.1-Flp and Ai65, induced at embryonic stages between E10 and E17 (Dlx1 mainly E12-E17) and read out at P28. The text compares same-day inductions in Nkx2.1-CreER;Ai14 mice (Fig 4). · IPs amplify laminar-restricted interneuron…; Figure legends

  4. ShownSuccessive bIP cohorts yield distinct interneuron types as well as layers. E12 gives L5 Martinotti, large basket and large dense arbor cells; E13 gives L4 cells; E14 gives L2/3 cells; E17 gives a rich population of chandelier cells (ChCs) and only two other types, horizontal and descending arbor cells.

    Sparse low-dose induction with morphological typing. E17 fate-mapped cells were bimodal in depth, and ChC, horizontal arbor and descending arbor cells together made up more than 90% of cells in three cortical areas. · Multiple temporal cohorts of bIPs diversify…; Figure legends

  5. SuggestedChCs are generated in two waves, one at the end of RGE neurogenesis and one at the end of RGL neurogenesis, and each wave settles outside-in. Deep-layer ChCs at E14 appear to come directly from RGE, not through Ascl1 IPs.

    Up to 75% of upper-layer cells from E10 RGE were ChCs. L2/3 ChC output peaked near E13 and E17; Gaussian fits gave R2 of 0.7866 and 0.8431, and the combined L2, L5 and L6 fit gave R2 0.6954. E14 Ascl1/Nkx2.1 induction labeled no deep-layer ChCs. · Two separate waves of ChCs are generated toward…; The outside-in pattern of ChCs lamination…; Figure legends

Methods, data and reproducibility

Inducible and intersectional genetic fate mapping (Nkx2.1-CreER, Ascl1-CreER, Dlx1-CreER, Nkx2.1-Flp) with short pulse-chase in embryos and P28 readout of interneuron laminar position and morphology. EdU/BrdU birthdating was combined with it, and cells were counted manually.

  • Fate-mapping cohorts of pregnant dams and offspring, with embryonic MGE pulse-chase sections and P28 cortex (mPFC, motor and somatosensory areas) · mouse · n = minimum 3 brains from 2 litters; 6 sections from 3 brains per time point
  • Whole brain image datasets shared on the Biolucida image server · mouse
Methods & tools
Nkx2.1-CreER, Ascl1-CreER, Dlx1-CreER, Nkx2.1-ires-FLP-O, Ai14, Ai65, EdU/BrdU birthdating, Neurolucida 11, Imaris 8.0.2, FIJI, GraphPad Prism, serial two-photon tomography
Reagents & environment
Analysis software: Neurolucida 11, Imaris 8.0.2, FIJI/ImageJ, GraphPad Prism; mice backcrossed 5 generations to Swiss-Webster background.
Reproducibility gaps
Whole brain images are on a Biolucida server with no URL given. Raw data and materials are available by request to the corresponding author. No code is described.
Limitations (4)
  • How far individual IPs are fate-restricted is unknown, for example whether one IP produces a pair of cells of the same morphological type such as ChCs. · stated by the authors
  • Nkx2.1-CreER appeared to label preferentially progenitors with high NKX2.1 levels, so Nkx2.1-low progenitors may evade early mapping. Some late ChCs could come directly from RGs, and Ascl1/Dlx1 overlap in bIPs is not resolved. · stated by the authors
  • Possible additional radial glia pools along the dorsal-ventral axis remain untested and would need large-scale clonal analysis at cellular resolution. · stated by the authors
  • Conclusions rest on population-level inducible labeling and birthdating with manual counts, not single-clone tracing. Graphed data need only three brains from two litters, and the ChC wave fits have modest R2 values. · noted in this summary

Who should read:Read this if you study cortical interneuron development or lineage tracing, or need a mouse genetic fate-mapping framework linking MGE progenitor types to interneuron types.

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