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High-mobility group nucleosomal binding domain 2 protects against microcephaly by maintaining global chromatin accessibility during corticogenesis.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2020 Jan 10; Vol. 295 (2), pp. 468-480. Date of Electronic Publication: 2019 Nov 07. - Publication Year :
- 2020
-
Abstract
- The surface area of the human cerebral cortex undergoes dramatic expansion during late fetal development, leading to cortical folding, an evolutionary feature not present in rodents. Microcephaly is a neurodevelopmental disorder defined by an abnormally small brain, and many gene mutations have been found to be associated with primary microcephaly. However, mouse models generated by ablating primary microcephaly-associated genes often fail to recapitulate the severe loss of cortical surface area observed in individuals with this pathology. Here, we show that a mouse model with deficient expression of high-mobility group nucleosomal binding domain 2 (HMGN2) manifests microcephaly with reduced cortical surface area and almost normal radial corticogenesis, with a pattern of incomplete penetrance. We revealed that altered cleavage plane and mitotic delay of ventricular radial glia may explain the rising ratio of intermediate progenitor cells to radial glia and the displacement of neural progenitor cells in microcephalic mutant mice. These led to decreased self-renewal of the radial glia and reduction in lateral expansion. Furthermore, we found that HMGN2 protected corticogenesis by maintaining global chromatin accessibility mainly at promoter regions, thereby ensuring the correct regulation of the transcriptome. Our findings underscore the importance of the regulation of chromatin structure in cortical development and highlight a mouse model with critical insights into the etiology of microcephaly.<br /> (© 2020 Gao et al.)
- Subjects :
- Animals
Cerebral Cortex metabolism
Female
Gene Deletion
Gene Expression Regulation, Developmental
HMGN2 Protein analysis
HMGN2 Protein genetics
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microcephaly genetics
Cerebral Cortex embryology
Chromatin Assembly and Disassembly
HMGN2 Protein metabolism
Microcephaly metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 295
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31699896
- Full Text :
- https://doi.org/10.1074/jbc.RA119.010616