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Dosage-dependent requirements of Magoh for cortical interneuron generation and survival.

ABSTRACT: Embryonic interneuron development underlies cortical function and its disruption contributes to neurological disease. Yet the mechanisms by which viable interneurons are produced from progenitors remain poorly understood. Here, we demonstrate dosage-dependent requirements of the exon junction complex component Magoh for interneuron genesis in mouse. Conditional Magoh ablation from interneuron progenitors, but not post-mitotic neurons, depletes cortical interneuron number through adulthood, with increased severity in homozygotes. Using live imaging, we discover that Magoh deficiency delays progenitor mitotic progression in a dosage-sensitive fashion, with 40% of homozygous progenitors failing to divide. This shows that Magoh is required in progenitors for both generation and survival of newborn progeny. Transcriptome analysis implicates p53 signaling; moreover, p53 ablation in Magoh haploinsufficient progenitors rescues apoptosis, completely recovering interneuron number. In striking contrast, in Magoh homozygotes, p53 loss fails to rescue interneuron number and mitotic delay, further implicating mitotic defects in interneuron loss. Our results demonstrate that interneuron development is intimately dependent upon progenitor mitosis duration and uncover a crucial post-transcriptional regulator of interneuron fate relevant for neurodevelopmental pathologies.This article has an associated 'The people behind the papers' interview.

SUBMITTER: Sheehan CJ

PROVIDER: S-EPMC6983725 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Dosage-dependent requirements of Magoh for cortical interneuron generation and survival.

Sheehan Charles J CJ McMahon John J JJ Serdar Lucas D LD Silver Debra L DL

Development (Cambridge, England) 20200113 1

Embryonic interneuron development underlies cortical function and its disruption contributes to neurological disease. Yet the mechanisms by which viable interneurons are produced from progenitors remain poorly understood. Here, we demonstrate dosage-dependent requirements of the exon junction complex component Magoh for interneuron genesis in mouse. Conditional Magoh ablation from interneuron progenitors, but not post-mitotic neurons, depletes cortical interneuron number through ad ...[more]

PMID: 31857347

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Project description:BackgroundCHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development.MethodsTo examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate.ResultsMild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice.ConclusionsTogether, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work.

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Dosage-dependent requirements of Magoh for cortical interneuron generation and survival.

Publications

Dosage-dependent requirements of <i>Magoh</i> for cortical interneuron generation and survival.

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