# Understanding the role of minor intron splicing in cortical development

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT STORRS · 2021 · $366,101

## Abstract

Microcephaly is a devastating developmental defect that can be caused by inherited mutations such as those
that inactivate the minor spliceosome or more recently Zika virus infections. In order to better understand the
underlying molecular and cellular defects that cause microcephaly, we must first understand the molecular and
cellular changes during normal development. The current proposal extends our finding that inactivation of the
minor spliceosome in our U11 conditional knockout (cKO) mouse crossed with Emx1-Cre results in
microcephaly observed at birth. We found that the primary cause of the microcephaly is loss of self-amplifying
radial glial cells (RGCs) and delayed death of intermediate progenitor cells (IPCs) without the corresponding
loss of neurons during early cortical development. Despite the complete loss of NPCs by E14, the developing
mutant cortex managed to produce layer IV neurons that are normally born at/after E14. We found that this
shift in neuron production is in conjunction with increased neurogenesis measured by EdU pulse/chase
experiments. Based on these complex phenotypes, we have proposed three aims to test the hypothesis that
minor spliceosome acts in a cell-type specific manner to inform cell cycle regulation, NPC competence, and
neuron production. Experiments proposed in aim 1a are designed to elucidate the precise cell-cycle regulation
of RGCs and IPCs and whether these two cell-types are undergoing self-amplifying or neurogenic cell
divisions. In aim 1b, we explore how the changes in U11-null RGCs and IPCs impact neuron production. In aim
2, the objective is to understand the molecular underpinning of the cell-type specific effect of U11 loss. The one
unique identifier of RGCs is that they divide rapidly compared to the IPCs, so the experiments proposed in aim
2a test the hypothesis that cell cycle speed confers susceptibility to loss of U11. Another possibility that the
experiments proposed in aim 2b is that each cell-type has a unique signature of minor intron-containing genes
(MIGs) that might make cells resistant/susceptible to U1 loss. Finally, RNAseq data showed activation of P53-
medated apoptosis pathway and cell cycle defect in the U11-null tissue. The experiments proposed in aim 3a
test whether rescuing cell cycle defect would prevent P53-mediated apoptosis or is P53-mediated apoptosis
independent of the cell cycle defect. Aim 3b tests the idea that if P53 is ablation, would it rescue cell cycle or
cell death and in turn rescue microcephaly. In all, we will find the role of this novel form of gene regulation in
cortical development and in turn provide insights into microcephaly observed in diseases such as
microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) and Roifman syndrome that are both
caused by defective minor spliceosome.

## Key facts

- **NIH application ID:** 10130006
- **Project number:** 5R01NS102538-04
- **Recipient organization:** UNIVERSITY OF CONNECTICUT STORRS
- **Principal Investigator:** RAHUL N KANADIA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $366,101
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130006

## Citation

> US National Institutes of Health, RePORTER application 10130006, Understanding the role of minor intron splicing in cortical development (5R01NS102538-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10130006. Licensed CC0.

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