p600 regulates spindle orientation in apical neural progenitors and contributes to neurogenesis in the developing neocortex
Open accessAbstract
Apical neural progenitors (aNPs) drive neurogenesis by means of a program consisting of self-proliferative and neurogenic divisions. The balance between these two manners of division sustains the pool of apical progenitors into late neurogenesis, thereby ensuring their availability to populate the brain with terminal cell types. Using knockout and in utero electroporation mouse models, we report a key role for the microtubule-associated protein 600 (p600) in the regulation of spindle orientation in aNPs, a cellular event that has been associated with cell fate and neurogenesis. We find that p600 interacts directly with the neurogenic protein Ndel1 and that aNPs knockout for p600, depleted of p600 by shRNA or expressing a Ndel1-binding p600 fragment all display randomized spindle orientation. Depletion of p600 by shRNA or expression of the Ndel1-binding p600 fragment also results in a decreased number of Pax6-positive aNPs and an increased number of Tbr2-positive basal progenitors destined to become neurons. These Pax6-positive aNPs display a tilted mitotic spindle. In mice wherein p600 is ablated in progenitors, the production of neurons is significantly impaired and this defect is associated with microcephaly. We propose a working model in which p600 controls spindle orientation in aNPs and discuss its implication for neurogenesis.
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Loss of the mouse ortholog of UBR4, called p600, in the developing brain impairs neurogenesis, resulting in microcephaly.
“Loss of the mouse ortholog (called p600) in the developing brain impairs neurogenesis, resulting in microcephaly [27].”
From Neandertal Introgression Sheds Light on Modern Human Endocranial Globularity (2019) · cites this paper as [27]
The Results section reports reduced Tuj-1 staining in p600SC−/− microcephalic brains and says this suggests decreased neurogenesis. The Discussion links reduced neuron production and microcephaly, but calls the evidence circumstantial and says microcephaly may have several causes. The claim states the causal link more definitively than the paper does. (LLM, conf=0.85)
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Neandertal Introgression Sheds Light on Modern Human Endocranial Globularity
Gunz, P., Tilot, A. K., Wittfeld, K., Teumer, A., Shapland, C. Y., van Erp, T. G. M., Dannemann, M., Vernot, B., Neubauer, S., Guadalupe, T., et al. (2019) · Current Biology · doi:10.1016/j.cub.2018.10.065 · Cited by 117 · see citing works
“Loss of the mouse ortholog (called p600) in the developing brain impairs neurogenesis, resulting in microcephaly [27].”
Backgroundp600/UBR4 in the central nervous system
Parsons, K., Nakatani, Y., & Nguyen, M. D. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1788-8 · Cited by 35 · see citing works
Self-citation
- Authors
- Belzil, C., Asada, N., Ishiguro, K.-I., Nakaya, T., Parsons, K., Pendolino, V., Neumayer, G., Mapelli, M., Nakatani, Y., Sanada, K., & Nguyen, M. D.
- Affiliations
- University of Calgary (CA)
- Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo (JP)
- Dana-Farber Cancer Institute (US)
- European Institute of Oncology (IT)
- Corresponding author
- Sanada, Kamon
- Nguyen, Minh Dang
- ORCID
- Venue
- Biology Open
- Publisher
- The Company of Biologists
- Published
- 2014-05-08
- Volume
- 3
- Issue
- 6
- Pages
- 475-485
- ISSN
- 2046-6390 (ISSN-L)
- PMC
- PMC4058081
- OpenAlex
- W2138890989
- Cited by
- 15
- References
- 45
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 1 · 2018: 3 · 2017: 1 · 2016: 2 · 2014: 2
- FWCI
- 0.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Biology Open (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- HighWire Press Open Archive (submittedVersion)
- Libraries and Cultural Resources (University of Calgary) (submittedVersion, cc-by-nc-sa)
- Funders
- University of Calgary
- Ministry of Education, Culture, Sports, Science and Technology
- Daiichi-Sankyo
- Ministero della Salute
- Associazione Italiana per la Ricerca sul Cancro
- Alberta Innovates
- Canadian Institutes of Health Research
- Japan Society for the Promotion of Science (26640005)
- National Cancer Institute
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- P600, spindle orientation, neurogenesis, neocortex development, Ndel1, microtubule-associated proteins, mitotic spindle, basal progenitors, Pax6, Tbr2, microcephaly, cell fate determination
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