A conserved molecular logic for neurogenesis to gliogenesis switch in the cerebral cortex

Author:

Liang Xiaoyi G.1,Hoang Kendy1,Meyerink Brandon L.23,Kc Pratiksha2,Paraiso Kitt4,Wang Li56,Jones Ian R.7,Zhang Yue1,Katzman Sol8ORCID,Finn Thomas S.1ORCID,Tsyporin Jeremiah1,Qu Fangyuan1,Chen Zhaoxu1ORCID,Visel Axel4910,Kriegstein Arnold56ORCID,Shen Yin67,Pilaz Louis-Jan23,Chen Bin1ORCID

Affiliation:

1. Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, CA 95064

2. Division of Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104

3. Department of Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57105

4. Environmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720

5. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143

6. Department of Neurology, University of California, San Francisco, CA 94143

7. Institute for Human Genetics, University of California, San Francisco, CA 94143

8. Genome Institute, University of California, Santa Cruz, CA 95064

9. U.S. Department of Energy Joint Genome Institute, Berkeley, CA 94720

10. Department of Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, CA 95343

Abstract

During development, neural stem cells in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Sonic Hedgehog (Shh) signaling promotes the cortical RGC lineage switch to generate cortical oligodendrocytes and OB interneurons. During this process, cortical RGCs generate intermediate progenitor cells that express critical gliogenesis genes Ascl1 , Egfr, and Olig2 . The increased Ascl1 expression and appearance of Egfr + and Olig2 + cortical progenitors are concurrent with the switch from excitatory neurogenesis to gliogenesis and OB interneuron neurogenesis in the cortex. While Shh signaling promotes Olig2 expression in the developing spinal cord, the exact mechanism for this transcriptional regulation is not known. Furthermore, the transcriptional regulation of Olig2 and Egfr has not been explored. Here, we show that in cortical progenitor cells, multiple regulatory programs, including Pax6 and Gli3, prevent precocious expression of Olig2 , a gene essential for production of cortical oligodendrocytes and astrocytes. We identify multiple enhancers that control Olig2 expression in cortical progenitors and show that the mechanisms for regulating Olig2 expression are conserved between the mouse and human. Our study reveals evolutionarily conserved regulatory logic controlling the lineage switch of cortical neural stem cells.

Funder

HHS | NIH | National Institute of Mental Health

HHS | NIH | National Institute of Neurological Disorders and Stroke

HHS | NIH | National Institute of Dental and Craniofacial Research

HHS | NIH | National Institute on Drug Abuse

Publisher

Proceedings of the National Academy of Sciences

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