A human-specific progenitor sub-domain extends neurogenesis and increases motor neuron production

Sumin Jang; Elias Gumnit; Hynek Wichterle

doi:10.1038/s41593-024-01739-8

A human-specific progenitor sub-domain extends neurogenesis and increases motor neuron production

Nat Neurosci. 2024 Oct;27(10):1945-1953. doi: 10.1038/s41593-024-01739-8. Epub 2024 Aug 29.

Authors

Sumin Jang¹, Elias Gumnit², Hynek Wichterle³

Affiliations

¹ Departments of Pathology and Cell Biology, Neuroscience, and Neurology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY, USA. [email protected].
² Departments of Pathology and Cell Biology, Neuroscience, and Neurology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY, USA.
³ Departments of Pathology and Cell Biology, Neuroscience, and Neurology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY, USA. [email protected].

PMID: 39210067
DOI: 10.1038/s41593-024-01739-8

Abstract

Neurogenesis lasts ~10 times longer in developing humans compared to mice, resulting in a >1,000-fold increase in the number of neurons in the CNS. To identify molecular and cellular mechanisms contributing to this difference, we studied human and mouse motor neurogenesis using a stem cell differentiation system that recapitulates species-specific scales of development. Comparison of human and mouse single-cell gene expression data identified human-specific progenitors characterized by coexpression of NKX2-2 and OLIG2 that give rise to spinal motor neurons. Unlike classical OLIG2⁺ motor neuron progenitors that give rise to two motor neurons each, OLIG2⁺/NKX2-2⁺ ventral motor neuron progenitors remain cycling longer, yielding ~5 times more motor neurons that are biased toward later-born, FOXP1-expressing subtypes. Knockout of NKX2-2 converts ventral motor neuron progenitors into classical motor neuron progenitors. Such new progenitors may contribute to the increased production of human motor neurons required for the generation of larger, more complex nervous systems.

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism
Cell Differentiation / physiology
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism
Gene Expression Regulation, Developmental
Homeobox Protein Nkx-2.2*
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
Mice
Motor Neurons* / metabolism
Motor Neurons* / physiology
Neural Stem Cells* / cytology
Neural Stem Cells* / metabolism
Neural Stem Cells* / physiology
Neurogenesis* / physiology
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Oligodendrocyte Transcription Factor 2* / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
Spinal Cord / cytology
Transcription Factors* / genetics
Transcription Factors* / metabolism
Zebrafish Proteins / genetics
Zebrafish Proteins / metabolism

Substances

Homeobox Protein Nkx-2.2
Transcription Factors
NKX2-2 protein, human
Nkx2-2 protein, mouse
Oligodendrocyte Transcription Factor 2
Forkhead Transcription Factors
Zebrafish Proteins
nkx2.2b protein, zebrafish
Repressor Proteins
Homeodomain Proteins
Foxp1 protein, mouse
OLIG2 protein, human
Nuclear Proteins
Basic Helix-Loop-Helix Transcription Factors

Abstract

MeSH terms

Substances

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