# Defective abscission and apoptosis of neural progenitor cells in a novel model of microcephaly

> **NIH NIH F30** · UNIVERSITY OF VIRGINIA · 2020 · $50,520

## Abstract

When neural progenitor cells (NPCs) fail to divide correctly at the right time and location, neurodevelopmental
disorders can occur, including gross abnormalities in the size and structure of the brain and more subtle
defects in neuronal layering and connectivity. One result of impaired NPC division in the cerebral cortex is
microcephaly. The majority of the genetic causes of microcephaly in humans are due to mutations that affect
parameters of mitosis in NPCs, but recently defects in cytokinesis have been implicated as well.
A novel model of microcephaly studied here, resulting from the loss of the kinesin-6 family member Kif20b, has
defects specifically in abscission, the last step in the cytokinesis phase of NPC division. Kif20b protein is
detected in the midbodies of NPCs, a structure that connects the two daughter cells' apical membranes until
mediating abscission. In Kif02b-/- cortex as well as in Kif20b-/- dissociated NPCs, midbody abnormalities,
signifying an abnormal abscission process, and apoptosis have been observed. A common mechanism in the
pathogenesis of many genetic and viral causes of microcephaly is p53-dependent apoptosis. However, it is not
known whether p53 is activated to cause apoptosis in response to defective abscission in any cell type. To test
whether apoptosis in Kif20b-/- mice is p53 dependent, we created mice double mutant for Kif20b and p53. New
preliminary data shows that the survival, apoptosis and decreased cortical thickness, at least at early ages, in
Kif20b-/- mice are rescued by p53 co-deletion. However, the relationship between midbody defects and p53
activation in Kif20b-/- NPCs is unknown. Additionally, the importance of abscission regulation to produce a
cortex of normal size and structure, apart from apoptosis prevention, is unclear. Correct midbody alignment is
important for epithelial structure in other organisms, and midbody inheritance has been shown to influence cell
fate, but the functional relevance of these observations for cortical development have not been demonstrated.
The survival of double mutant mice for many months past birth provides an opportunity to examine the
consequences of abnormal abscission for postnatal cortical development. My specific hypothesis is that p53
is activated in response to impaired abscission in Kif20b-/- NPCs to cause apoptosis, and that this
response is important to prevent abnormalities in cortical size and structure. To test this hypothesis, I
propose to study Kif20b-/- p53-/- mice in vivo and Kif20b-/- NPCs cultured in vitro with and without inhibition of
p53. With these techniques and using fixed and live imaging experiments, I will complete the following aims:
Aim 1) Determine the relationship between abscission defects and p53-dependent apoptosis in Kif20b-/- mice.
Aim 2) Investigate the consequence of Kif20b loss for NPCs when p53 is co-deleted.
The proposed research is significant in that it will bridge the gap in our knowledge of how apoptosis is
regulat...

## Key facts

- **NIH application ID:** 9977259
- **Project number:** 5F30HD093290-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Jessica Neville Little
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-08-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977259

## Citation

> US National Institutes of Health, RePORTER application 9977259, Defective abscission and apoptosis of neural progenitor cells in a novel model of microcephaly (5F30HD093290-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9977259. Licensed CC0.

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