LIF signaling regulates outer radial glial to interneuron fate during human cortical development

Madeline G. Andrews; Clara Siebert; Li Wang; Matthew L. White; Jayden Ross; Raul Morales; Megan Donnay; Gradi Bamfonga; Tanzila Mukhtar; Arpana Arjun McKinney; Kaila Gemenes; Shaohui Wang; Qiuli Bi; Elizabeth E. Crouch; Neelroop Parikshak; Georgia Panagiotakos; Eric Huang; Aparna Bhaduri; Arnold R. Kriegstein

doi:10.1016/j.stem.2023.08.009

LIF signaling regulates outer radial glial to interneuron fate during human cortical development

Madeline G. Andrews, Clara Siebert, Li Wang, Matthew L. White, Jayden Ross, Raul Morales, Megan Donnay, Gradi Bamfonga, Tanzila Mukhtar, Arpana Arjun McKinney, Kaila Gemenes, Shaohui Wang, Qiuli Bi, Elizabeth E. Crouch, Neelroop Parikshak, Georgia Panagiotakos, Eric Huang, Aparna Bhaduri, Arnold R. Kriegstein

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

Radial glial (RG) development is essential for cerebral cortex growth and organization. In humans, the outer radial glia (oRG) subtype is expanded and gives rise to diverse neurons and glia. However, the mechanisms regulating oRG differentiation are unclear. oRG cells express leukemia-inhibitory factor (LIF) receptors during neurogenesis, and consistent with a role in stem cell self-renewal, LIF perturbation impacts oRG proliferation in cortical tissue and organoids. Surprisingly, LIF treatment also increases the production of inhibitory interneurons (INs) in cortical cultures. Comparative transcriptomic analysis identifies that the enhanced IN population resembles INs produced in the caudal ganglionic eminence. To evaluate whether INs could arise from oRGs, we isolated primary oRG cells and cultured them with LIF. We observed the production of INs from oRG cells and an increase in IN abundance following LIF treatment. Our observations suggest that LIF signaling regulates the capacity of oRG cells to generate INs.

Original language	English
Pages (from-to)	1382-1391.e5
Journal	Cell Stem Cell
Volume	30
Issue number	10
DOIs	https://doi.org/10.1016/j.stem.2023.08.009
State	Published - 5 Oct 2023

Keywords

cerebral cortex
human development
inhibitory interneurons
mechanisms of differentiation
neural progenitors
neurodevelopment
organoid models
pluripotent stem cells
radial glia
signaling mechanisms

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10.1016/j.stem.2023.08.009

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Andrews, M. G., Siebert, C., Wang, L., White, M. L., Ross, J., Morales, R., Donnay, M., Bamfonga, G., Mukhtar, T., McKinney, A. A., Gemenes, K., Wang, S., Bi, Q., Crouch, E. E., Parikshak, N., Panagiotakos, G., Huang, E., Bhaduri, A., & Kriegstein, A. R. (2023). LIF signaling regulates outer radial glial to interneuron fate during human cortical development. Cell Stem Cell, 30(10), 1382-1391.e5. https://doi.org/10.1016/j.stem.2023.08.009

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title = "LIF signaling regulates outer radial glial to interneuron fate during human cortical development",

abstract = "Radial glial (RG) development is essential for cerebral cortex growth and organization. In humans, the outer radial glia (oRG) subtype is expanded and gives rise to diverse neurons and glia. However, the mechanisms regulating oRG differentiation are unclear. oRG cells express leukemia-inhibitory factor (LIF) receptors during neurogenesis, and consistent with a role in stem cell self-renewal, LIF perturbation impacts oRG proliferation in cortical tissue and organoids. Surprisingly, LIF treatment also increases the production of inhibitory interneurons (INs) in cortical cultures. Comparative transcriptomic analysis identifies that the enhanced IN population resembles INs produced in the caudal ganglionic eminence. To evaluate whether INs could arise from oRGs, we isolated primary oRG cells and cultured them with LIF. We observed the production of INs from oRG cells and an increase in IN abundance following LIF treatment. Our observations suggest that LIF signaling regulates the capacity of oRG cells to generate INs.",

keywords = "cerebral cortex, human development, inhibitory interneurons, mechanisms of differentiation, neural progenitors, neurodevelopment, organoid models, pluripotent stem cells, radial glia, signaling mechanisms",

author = "Andrews, {Madeline G.} and Clara Siebert and Li Wang and White, {Matthew L.} and Jayden Ross and Raul Morales and Megan Donnay and Gradi Bamfonga and Tanzila Mukhtar and McKinney, {Arpana Arjun} and Kaila Gemenes and Shaohui Wang and Qiuli Bi and Crouch, {Elizabeth E.} and Neelroop Parikshak and Georgia Panagiotakos and Eric Huang and Aparna Bhaduri and Kriegstein, {Arnold R.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = oct,

day = "5",

doi = "10.1016/j.stem.2023.08.009",

language = "English",

volume = "30",

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Andrews, MG, Siebert, C, Wang, L, White, ML, Ross, J, Morales, R, Donnay, M, Bamfonga, G, Mukhtar, T, McKinney, AA, Gemenes, K, Wang, S, Bi, Q, Crouch, EE, Parikshak, N, Panagiotakos, G, Huang, E, Bhaduri, A & Kriegstein, AR 2023, 'LIF signaling regulates outer radial glial to interneuron fate during human cortical development', Cell Stem Cell, vol. 30, no. 10, pp. 1382-1391.e5. https://doi.org/10.1016/j.stem.2023.08.009

TY - JOUR

T1 - LIF signaling regulates outer radial glial to interneuron fate during human cortical development

AU - Andrews, Madeline G.

AU - Siebert, Clara

AU - Wang, Li

AU - White, Matthew L.

AU - Ross, Jayden

AU - Morales, Raul

AU - Donnay, Megan

AU - Bamfonga, Gradi

AU - Mukhtar, Tanzila

AU - McKinney, Arpana Arjun

AU - Gemenes, Kaila

AU - Wang, Shaohui

AU - Bi, Qiuli

AU - Crouch, Elizabeth E.

AU - Parikshak, Neelroop

AU - Panagiotakos, Georgia

AU - Huang, Eric

AU - Bhaduri, Aparna

AU - Kriegstein, Arnold R.

PY - 2023/10/5

Y1 - 2023/10/5

N2 - Radial glial (RG) development is essential for cerebral cortex growth and organization. In humans, the outer radial glia (oRG) subtype is expanded and gives rise to diverse neurons and glia. However, the mechanisms regulating oRG differentiation are unclear. oRG cells express leukemia-inhibitory factor (LIF) receptors during neurogenesis, and consistent with a role in stem cell self-renewal, LIF perturbation impacts oRG proliferation in cortical tissue and organoids. Surprisingly, LIF treatment also increases the production of inhibitory interneurons (INs) in cortical cultures. Comparative transcriptomic analysis identifies that the enhanced IN population resembles INs produced in the caudal ganglionic eminence. To evaluate whether INs could arise from oRGs, we isolated primary oRG cells and cultured them with LIF. We observed the production of INs from oRG cells and an increase in IN abundance following LIF treatment. Our observations suggest that LIF signaling regulates the capacity of oRG cells to generate INs.

AB - Radial glial (RG) development is essential for cerebral cortex growth and organization. In humans, the outer radial glia (oRG) subtype is expanded and gives rise to diverse neurons and glia. However, the mechanisms regulating oRG differentiation are unclear. oRG cells express leukemia-inhibitory factor (LIF) receptors during neurogenesis, and consistent with a role in stem cell self-renewal, LIF perturbation impacts oRG proliferation in cortical tissue and organoids. Surprisingly, LIF treatment also increases the production of inhibitory interneurons (INs) in cortical cultures. Comparative transcriptomic analysis identifies that the enhanced IN population resembles INs produced in the caudal ganglionic eminence. To evaluate whether INs could arise from oRGs, we isolated primary oRG cells and cultured them with LIF. We observed the production of INs from oRG cells and an increase in IN abundance following LIF treatment. Our observations suggest that LIF signaling regulates the capacity of oRG cells to generate INs.

KW - cerebral cortex

KW - human development

KW - inhibitory interneurons

KW - mechanisms of differentiation

KW - neural progenitors

KW - neurodevelopment

KW - organoid models

KW - pluripotent stem cells

KW - radial glia

KW - signaling mechanisms

UR - http://www.scopus.com/inward/record.url?scp=85173459428&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2023.08.009

DO - 10.1016/j.stem.2023.08.009

M3 - Article

C2 - 37673072

AN - SCOPUS:85173459428

SN - 1934-5909

VL - 30

SP - 1382-1391.e5

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 10

ER -

LIF signaling regulates outer radial glial to interneuron fate during human cortical development

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Keywords

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