# Linking the molecular operations of cohesin to its physiological activity in the mammalian brain

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $619,474

## Abstract

PROJECT SUMMARY
Mammalian genomes are organized into loops and topologically associated domains by the cohesin protein
complex. The formation of these structures has suggested models for how DNA regulatory elements, such as
enhancers and promoters, are spatially arranged to coordinate gene expression. However, testing these models
and their implications in cellular function and fate has been challenging due to the lack of systems for
interrogating the activity of cohesin in vivo. Using mouse olfactory sensory neurons and serotonergic neurons
from the raphe nuclei, post-mitotic cells in which the role of cohesin in genome function can be uncoupled from
its role in sister chromatin cohesion, we recently uncovered that cohesin and its unloader WAPL play a critical
role in the development of the central nervous system by regulating the expression of clustered Protocadherin
(Pcdh) genes. In this proposal, we aim to leverage the Pcdh gene cluster as a new paradigm to study the
molecular underpinnings of cohesin activity and its dynamics in governing the generation of neuronal cell surface
diversity during brain development. Specifically, we propose to understand the role of auxiliary proteins to the
cohesin complex in regulating cohesin dynamics and Pcdh gene expression in vivo. Finally, we aim to link the
molecular operations of cohesin and its protein regulators to neural wiring and neural circuit assembly. The
findings from our proposed studies are poised to generate new hypotheses for how genome architecture is
coupled to gene expression in mammalian cells. They will provide an unprecedented view of neural wiring across
scales, linking cell-type-specific regulation of genome structure to neural wiring during brain development.
Finally, they will generate insights into developmental and intellectual disorders known as cohesinopathies,
where dysregulation of the Pcdh genes is linked to improper cohesin actions.

## Key facts

- **NIH application ID:** 10944724
- **Project number:** 1R01NS138619-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Daniele Canzio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $619,474
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10944724

## Citation

> US National Institutes of Health, RePORTER application 10944724, Linking the molecular operations of cohesin to its physiological activity in the mammalian brain (1R01NS138619-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10944724. Licensed CC0.

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