ATRX is required for maintenance of the neuroprogenitor cell pool in the embryonic mouse brain
Open accessAbstract
Mutations in the alpha-thalassemia mental retardation X-linked (ATRX) gene cause a spectrum of abnormalities including intellectual disability, developmental delay, seizures, and microcephaly. The ATRX protein is highly enriched at heterochromatic repetitive sequences adjacent to the centromere, and ATRX depletion results in chromosome congression, segregation, and cohesion defects. Here, we show that Cre-mediated inactivation of Atrx in the embryonic mouse (Mus musculus) brain results in expansion of cerebral cortical layer VI, and a concurrent thinning of layers II–IV. We observed increased cell cycle exit during early-mid neurogenesis, and a depletion of apical progenitors by late neurogenesis in the Atrx-null neocortex, explaining the disproportionate layering. Premature differentiation was associated with an increased generation of outer radial glia (oRG) and TBR2-expressing basal progenitors, as well as increased generation of early-born post-mitotic projection neurons. Atrx deletion also reduced the fidelity of mitotic spindle orientation in apical progenitors, where mutant cells were often oriented at non-parallel angles of division relative to the ventricular surface. We conclude that ATRX is required for correct lamination of the mouse neocortex by regulating the timing of neuroprogenitor cell differentiation.
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More changes related to microcephaly are found on both lineages, for example in ATRX or CASC5.
“Nevertheless, more changes related to microcephaly are found on both lineages, for example in ATRX73 or CASC574 (Supplementary Information 3).”
From A catalog of single nucleotide changes distinguishing modern humans from archaic hominins (2019) · cites this paper as [73]
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- Authors
- Ritchie, K., Watson, L. A., Davidson, B., Jiang, Y., & Bérubé, N. G.
- Affiliations
- Western University (CA)
- Corresponding author
- Bérubé, Nathalie G.
- Venue
- Biology Open
- Publisher
- The Company of Biologists
- Published
- 2014-11-13
- Volume
- 3
- Issue
- 12
- Pages
- 1158-1163
- ISSN
- 2046-6390 (ISSN-L)
- PMC
- PMC4265753
- OpenAlex
- W2114526935
- Cited by
- 39
- References
- 23
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 5 · 2018: 2 · 2017: 2 · 2016: 8 · 2015: 3
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Biology Open (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Scholarship@Western (Western University) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- ATRX, neural progenitor cells, cortical lamination, neocortex development, embryonic mouse brain, apical progenitors, outer radial glia, basal progenitors, mitotic spindle orientation, cell cycle exit, premature differentiation, centromeric heterochromatin
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