Pax6 limits the competence of developing cerebral cortical cells to respond to inductive intercellular signals

The development of stable specialized cell types in multicellular organisms relies on mechanisms controlling inductive intercellular signals and the competence of cells to respond to such signals. In developing cerebral cortex, progenitors generate only glutamatergic excitatory neurons despite being...

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Published in:	PLoS biology Vol. 20; no. 9; p. e3001563
Main Authors:	Manuel, Martine, Tan, Kai Boon, Kozic, Zrinko, Molinek, Michael, Marcos, Tiago Sena, Razak, Maizatul Fazilah Abd, Dobolyi, Dániel, Dobie, Ross, Henderson, Beth E P, Henderson, Neil C, Chan, Wai Kit, Daw, Michael I, Mason, John O, Price, David J
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 06-09-2022 Public Library of Science (PLoS)
Subjects:	Age Archives & records Binding sites Biology and Life Sciences Bone morphogenetic protein 4 Brain cells Cellular signal transduction Cerebral cortex Cerebral Cortex - metabolism Deletion Eye Proteins - metabolism Gene expression Gene Expression Regulation, Developmental Genetic aspects Glutamatergic transmission Homeodomain Proteins - metabolism Medicine and Health Sciences Neural stem cells Neurogenesis Neurons Paired Box Transcription Factors - genetics Paired Box Transcription Factors - metabolism Pax6 protein PAX6 Transcription Factor - genetics PAX6 Transcription Factor - metabolism Physiological aspects Progenitor cells Proteins Regional development Repressor Proteins - metabolism Research and Analysis Methods Risk reduction Side effects Transcription factors United Kingdom
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Summary:	The development of stable specialized cell types in multicellular organisms relies on mechanisms controlling inductive intercellular signals and the competence of cells to respond to such signals. In developing cerebral cortex, progenitors generate only glutamatergic excitatory neurons despite being exposed to signals with the potential to initiate the production of other neuronal types, suggesting that their competence is limited. Here, we tested the hypothesis that this limitation is due to their expression of transcription factor Pax6. We used bulk and single-cell RNAseq to show that conditional cortex-specific Pax6 deletion from the onset of cortical neurogenesis allowed some progenitors to generate abnormal lineages resembling those normally found outside the cortex. Analysis of selected gene expression showed that the changes occurred in specific spatiotemporal patterns. We then compared the responses of control and Pax6-deleted cortical cells to in vivo and in vitro manipulations of extracellular signals. We found that Pax6 loss increased cortical progenitors' competence to generate inappropriate lineages in response to extracellular factors normally present in developing cortex, including the morphogens Shh and Bmp4. Regional variation in the levels of these factors could explain spatiotemporal patterns of fate change following Pax6 deletion in vivo. We propose that Pax6's main role in developing cortical cells is to minimize the risk of their development being derailed by the potential side effects of morphogens engaged contemporaneously in other essential functions.
Bibliography:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current address: Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom The authors have declared that no competing interests exist.
ISSN:	1545-7885 1544-9173 1545-7885
DOI:	10.1371/journal.pbio.3001563