# Neural Progenitor Environmental Sense, Mitotic Time, and Mitotic Location and their Effects on Corticogenesis

> **NIH NIH F99** · JOHNS HOPKINS UNIVERSITY · 2024 · $49,974

## Abstract

Project Summary: F99 Phase
Primary hereditary microcephaly, gray matter heterotopia, autism spectrum disorder, bipolar disorder, and
schizophrenia affect millions of individuals worldwide and have all been linked to improper neurodevelopment, a
tightly regulated process where temporal and spatial regulation of the cell cycle is integral to the production of
the right number and type of cells in the brain. Temporal dysregulation such as significant mitotic delay in cortical
progenitors has been known to result in Tp53 induced apoptosis in response to activation of the Mitotic
Surveillance Pathway (MSP), depleting the neural progenitor pool and reducing the number of neurons
produced. Spatial dysregulation, such as alterations of location where progenitors divide within the developing
cortex, has been shown to alter cortical organization. Mutations in genes involved in cilia biogenesis, affecting
neural progenitor signaling, have been shown to result in an array of conditions such as macrocephaly and
polymicrogyria. I use multiple mutant mouse models that affect the centrosome-related functions of progenitor
division speed, cilia production, and neocortical localization to better understand how dysregulation of those
processes affect cell fate and cortical organization both when the MSP is active and inactive. The amount of time
mitosis is delayed in my models varies depending on the allele that is knocked out, with a subset of the mitotically
delayed models additionally having their progenitors delocalized and spread throughout the developing cortex. I
will use these mouse models to: Aim 1A: Characterize how these genetic manipulations affect cortical
development using gross and immunofluorescent analysis techniques. Aim 1B: Perform single-cell RNA
sequencing in conjunction with CFSE and EdU labeling, elucidating the transcriptome of all cycling progenitors
(EdU), and progenitors based on the number of divisions it has gone through since they were in contact with the
ventricular surface (CFSE). Aim 1C: Investigate how location of progenitors influence gene expression by using
the spatial transcriptomic method, MERFISH. Thus, I hypothesize that the centrosome-related functions of
progenitor division speed, cilia production, and localization ensure spatiotemporal regulation of
corticogenesis, and when perturbed, uniquely change neural progenitor expression profiles, altering
fate specification and cortical organization. Having both active and inactive MSP models will allow the
investigation of progenitor fate in two different directions. With an active MSP, the time progenitors are delayed
in mitosis will be linked with the number and type of progenitors that are able to avoid MSP activation and
differentiate, illuminating which mature neuron types are produced for a given mitotic delay time. With the inactive
MSP models, all progenitors will be able to proliferate and differentiate. I will be able to link alterations in time
and location of progeni...

## Key facts

- **NIH application ID:** 11001618
- **Project number:** 1F99NS139554-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Zachary Bryant Nicholas
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $49,974
- **Award type:** 1
- **Project period:** 2024-07-12 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11001618

## Citation

> US National Institutes of Health, RePORTER application 11001618, Neural Progenitor Environmental Sense, Mitotic Time, and Mitotic Location and their Effects on Corticogenesis (1F99NS139554-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11001618. Licensed CC0.

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