Multipotent radial glia progenitors and fate-restricted intermediate progenitors sequentially generate diverse cortical interneuron types

SUMMARYGABAergic interneurons deploy numerous inhibitory mechanisms that regulate cortical circuit operation, but the developmental programs that generate diverse interneuron types remain not 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). 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 is restricted to the caudal MGE, has limited neurogenic capacity, and involves mostly apical IPs. The second wave initiates throughout the MGE 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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Radial glial lineage progression and differential intermediate progenitor amplification underlie striatal compartments and circuit organization

10.1101/244327 ◽

2018 ◽

Cited By ~ 2

Author(s):

Sean M. Kelly ◽

Ricardo Raudales ◽

Miao He ◽

Jannifer Lee ◽

Yongsoo Kim ◽

...

Keyword(s):

Basal Ganglia ◽

Late Phase ◽

Projection Neurons ◽

Limited Capacity ◽

Indirect Pathway ◽

Intermediate Progenitors ◽

Lateral Ganglionic Eminence ◽

Glial Progenitors ◽

Radial Glial ◽

Glial Lineage

SUMMARYThe circuitry of the striatum is characterized by two organizational plans: the division into striosome and matrix compartments, thought to mediate evaluation and action, and the direct and indirect pathways, thought to promote or suppress behavior. The developmental origins of and relationships between these organizations are unknown, leaving a conceptual gap in understanding the cortico-basal ganglia system. Through genetic fate mapping, we demonstrate that striosome-matrix compartmentalization arises from a lineage program embedded in lateral ganglionic eminence radial glial progenitors mediating neurogenesis through two distinct types of intermediate progenitors (IPs). The early phase of this program produces striosomal spiny projection neurons (SPNs) through fate-restricted apical IPs (aIPSs) with limited capacity; the late phase produces matrix SPNs through fate-restricted basal IPs (bIPMs) with expanded capacity. Remarkably, direct and indirect pathway SPNs arise within both aIPS and bIPM pools, suggesting that striosome-matrix architecture is the fundamental organizational plan of basal ganglia circuitry organization.

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FGF2 modulates simultaneously the mode, the rate of division and the growth fraction in cultures of Radial Glia

10.1101/707463 ◽

2019 ◽

Author(s):

Mario Ledesma-Terrón ◽

Nuria Peralta-Cañadas ◽

David G. Míguez

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Radial Glia ◽

Numerical Models ◽

Fibroblast Growth Factor 2 ◽

Growth Fraction ◽

Fibroblast Growth ◽

Glial Progenitors ◽

Radial Glial

ABSTRACTRadial Glial progenitors in the mammalian developing neocortex have been shown to follow a deterministic differentiation program restricted to an asymmetric-only mode of division. This feature seems incompatible with their well known ability to expand in number when cultured in vitro, driven by Fibroblast Growth Factor 2 and other mitogenic signals. The changes in their differentiation dynamics that allow this transition from in vivo asymmetric-only division mode to an in vitro self-renewing culture have not been fully characterized. Here we combine experiments of Radial Glia cultures with theory and numerical models to show that Fibroblast Growth Factor 2 has a triple effect by simultaneously increasing the growth fraction, promoting symmetric divisions and shortening the length of the cell cycle. This combined effect of Fibroblast Growth Factor 2 in the differentiation dynamics of Radial Glial progenitors partner to establish and sustain a pool of rapidly proliferating in vitro pool of Radial Glial progenitors.

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Transcriptional priming as a conserved mechanism of lineage diversification in the developing mouse and human neocortex

Science Advances ◽

10.1126/sciadv.abd2068 ◽

2020 ◽

Vol 6 (45) ◽

pp. eabd2068

Author(s):

Zhen Li ◽

William A. Tyler ◽

Ella Zeldich ◽

Gabriel Santpere Baró ◽

Mayumi Okamoto ◽

...

Keyword(s):

Glial Cells ◽

Radial Glia ◽

Radial Glial Cells ◽

Human Neocortex ◽

Intermediate Progenitors ◽

Cell Diversity ◽

Radial Glial ◽

The Rich ◽

Lineage Diversification

How the rich variety of neurons in the nervous system arises from neural stem cells is not well understood. Using single-cell RNA-sequencing and in vivo confirmation, we uncover previously unrecognized neural stem and progenitor cell diversity within the fetal mouse and human neocortex, including multiple types of radial glia and intermediate progenitors. We also observed that transcriptional priming underlies the diversification of a subset of ventricular radial glial cells in both species; genetic fate mapping confirms that the primed radial glial cells generate specific types of basal progenitors and neurons. The different precursor lineages therefore diversify streams of cell production in the developing murine and human neocortex. These data show that transcriptional priming is likely a conserved mechanism of mammalian neural precursor lineage specialization.

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FGF2 modulates simultaneously the mode, the rate of division and the growth fraction in cultures of radial glia

Development ◽

10.1242/dev.189712 ◽

2020 ◽

Vol 147 (14) ◽

pp. dev189712

Author(s):

Mario Ledesma-Terrón ◽

Nuria Peralta-Cañadas ◽

David G. Míguez

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Branching Process ◽

Radial Glia ◽

Fibroblast Growth Factor 2 ◽

Growth Fraction ◽

Fibroblast Growth ◽

Glial Progenitors ◽

Radial Glial

ABSTRACTRadial glial progenitors in the mammalian developing neocortex have been shown to follow a deterministic differentiation program restricted to an asymmetric-only mode of division. This feature seems incompatible with their well-known ability to increase in number when cultured in vitro, driven by fibroblast growth factor 2 and other mitogenic signals. The changes in their differentiation dynamics that allow this transition from in vivo asymmetric-only division mode to an in vitro self-renewing culture have not been fully characterized. Here, we combine experiments of radial glia cultures with numerical models and a branching process theoretical formalism to show that fibroblast growth factor 2 has a triple effect by simultaneously increasing the growth fraction, promoting symmetric divisions and shortening the length of the cell cycle. These combined effects partner to establish and sustain a pool of rapidly proliferating radial glial progenitors in vitro. We also show that, in conditions of variable proliferation dynamics, the branching process tool outperforms other commonly used methods based on thymidine analogs, such as BrdU and EdU, in terms of accuracy and reliability.

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Distinct progenitor behavior underlying neocortical gliogenesis related to tumorigenesis

10.1101/2020.10.13.338459 ◽

2020 ◽

Author(s):

Zhongfu Shen ◽

Yang Lin ◽

Jiajun Yang ◽

David J. Jörg ◽

Yuwei Peng ◽

...

Keyword(s):

Progenitor Cell ◽

Neurofibromatosis Type ◽

Primary Brain Tumor ◽

Precursor Cells ◽

Cell Behavior ◽

Neocortical Neurons ◽

Glial Progenitors ◽

Radial Glial ◽

Oligodendrocyte Precursor

SUMMARYRadial glial progenitors (RGPs) are responsible for producing the vast majority of neurons and glia in the neocortex. While RGP behavior and progressive generation of neocortical neurons have been delineated, the exact process of neocortical gliogenesis remains elusive. Here, we report the precise progenitor cell behavior and gliogenesis program at single-cell resolution in the mouse neocortex. RGPs transition from neurogenesis to gliogenesis progressively, producing astrocytes, oligodendrocytes, or both in well-defined propensities of 60%:15%:25%, respectively, via fate-restricted “intermediate” precursor cells. While the total number of precursor cells generated by individual RGPs appears stochastic, the output of individual precursor cells exhibit clear patterns in number and subtype, and form discrete local subclusters. Clonal loss of tumor suppressor Neurofibromatosis type 1 leads to excessive production of glia selectively, especially oligodendrocyte precursor cells. These results delineate the cellular program of neocortical gliogenesis quantitatively and suggest the cellular and lineage origin of primary brain tumor.

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Topical Review: Neuronal Migration in Cortical Development

Journal of Child Neurology ◽

10.1177/08830738040190030201 ◽

2004 ◽

Vol 19 (3) ◽

pp. 274-279

Author(s):

Shigeaki Kanatani ◽

Hidenori Tabata ◽

Kazunori Nakajima

Keyword(s):

Neuronal Migration ◽

Radial Glia ◽

Asymmetric Cell Division ◽

Time Lapse ◽

Radial Glial Cells ◽

Daughter Cells ◽

Radial Glial ◽

Time Lapse Imaging ◽

Mitotic Behavior

Cortical formation in the developing brain is a highly complicated process involving neuronal production (through symmetric or asymmetric cell division) interaction of radial glia with neuronal migration, and multiple modes of neuronal migration. It has been convincingly demonstrated by numerous studies that radial glial cells are neural stem cells. However, the processes by which neurons arise from radial glia and migrate to their final destinations in vivo are not yet fully understood. Recent studies using time-lapse imaging of neuronal migration are giving investigators an increasingly more detailed understanding of the mitotic behavior of radial glia and the migrating behavior of their daughter cells. In this review, we describe recent progress in elucidating neuronal migration in brain formation and how neuronal migration is disturbed by mutations in genes that control this process. ( J Child Neurol 2005;20:274—279).

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Enhanced FGFR3 activity in postmitotic principal neurons during brain development results in cortical dysplasia and axonal tract abnormality

Scientific Reports ◽

10.1038/s41598-020-75537-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Jui-Yen Huang ◽

Bruna Baumgarten Krebs ◽

Marisha Lynn Miskus ◽

May Lin Russell ◽

Eamonn Patrick Duffy ◽

...

Keyword(s):

Neurological Disorders ◽

Radial Glia ◽

Sequencing Analysis ◽

Axonal Pathfinding ◽

Glutamatergic Neurons ◽

Alternative Approach ◽

Postmitotic Neurons ◽

Cycle Regulation ◽

The Impact ◽

Inside Out

Abstract Abnormal levels of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) have been detected in various neurological disorders. The potent impact of FGF-FGFR in multiple embryonic developmental processes makes it challenging to elucidate their roles in postmitotic neurons. Taking an alternative approach to examine the impact of aberrant FGFR function on glutamatergic neurons, we generated a FGFR gain-of-function (GOF) transgenic mouse, which expresses constitutively activated FGFR3 (FGFR3K650E) in postmitotic glutamatergic neurons. We found that GOF disrupts mitosis of radial-glia neural progenitors (RGCs), inside-out radial migration of post-mitotic glutamatergic neurons, and axonal tract projections. In particular, late-born CUX1-positive neurons are widely dispersed throughout the GOF cortex. Such a cortical migration deficit is likely caused, at least in part, by a significant reduction of the radial processes projecting from RGCs. RNA-sequencing analysis of the GOF embryonic cortex reveals significant alterations in several pathways involved in cell cycle regulation and axonal pathfinding. Collectively, our data suggest that FGFR3 GOF in postmitotic neurons not only alters axonal growth of postmitotic neurons but also impairs RGC neurogenesis and radial glia processes.

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Radial glial cells in the adult dentate gyrus: what are they and where do they come from?

F1000Research ◽

10.12688/f1000research.12684.1 ◽

2018 ◽

Vol 7 ◽

pp. 277 ◽

Cited By ~ 32

Author(s):

Daniel A. Berg ◽

Allison M. Bond ◽

Guo-li Ming ◽

Hongjun Song

Keyword(s):

Stem Cells ◽

Dentate Gyrus ◽

Radial Glia ◽

Neural Precursor Cells ◽

Neural Precursor ◽

Subgranular Zone ◽

Adult Neural Stem Cell ◽

Radial Glial Cells ◽

Embryonic Origin ◽

Radial Glial

Adult neurogenesis occurs in the dentate gyrus in the mammalian hippocampus. These new neurons arise from neural precursor cells named radial glia-like cells, which are situated in the subgranular zone of the dentate gyrus. Here, we review the emerging topic of precursor heterogeneity in the adult subgranular zone. We also discuss how this heterogeneity may be established during development and focus on the embryonic origin of the dentate gyrus and radial glia-like stem cells. Finally, we discuss recently developed single-cell techniques, which we believe will be critical to comprehensively investigate adult neural stem cell origin and heterogeneity.

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