# MOLECULAR ANALYSIS OF HINDBRAIN DEVELOPMENT

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $369,767

## Abstract

Formation of the CNS during embryogenesis requires the de novo initiation of neural
gene expression in embryonic ectoderm. E.g., the Hoxb1a and Hoxb1b transcription
factors (TFs) are required for zebrafish hindbrain development, but it is unclear how they
activate gene expression. In particular, embryonic chromatin is compacted, making
regulatory elements inaccessible to most TFs. We find that Prep and Pbx (two TFs
identified as cofactors to Hox proteins) occupy genetic loci prior to zygotic genome
activation – many hours before Hox proteins are active and well before hindbrain
development is initiated. Also, Prep:Pbx occupied sites co-localize with binding sites for
the NFY TF. We hypothesize that maternally deposited Prep:Pbx cooperates with
NFY to open chromatin at hindbrain genes. This process exposes binding sites for
hindbrain-specific TFs (e.g. Hox proteins) to drive gene expression in the hindbrain.
 There are three aims of our proposed work: First we will disrupt Prep:Pbx and NFY
function to determine if they modulate the chromatin state. Second, we will determine if
Prep:Pbx-mediated chromatin changes promote binding by Hoxb1b to create hindbrain-
specific enhancers. Lastly, we will determine how such enhancers drive hindbrain-specific
gene expression.
 This work is relevant for several reasons. First, it is important to understand
hindbrain development per se (as defects give rise to ataxias etc.). Second, our results
will be applicable to understanding hox function in general, which is important since
other hox genes are involved in hindbrain development (and many other cell fate
decisions). Additionally, prep and pbx are proto-oncogenes and it is likely that their ability
to drive de novo gene expression will explain some of their oncogenic potential. Lastly,
our experiments will show how genes can be activated in inaccessible chromatin. This will
be applicable to targeted differentiation/reprogramming of stem or precursor cells – hence
our work will also inform efforts to generate specific cell types for clinical applications.

## Key facts

- **NIH application ID:** 9751401
- **Project number:** 5R01NS038183-21
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Charles G Sagerstrom
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $369,767
- **Award type:** 5
- **Project period:** 1998-12-03 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9751401

## Citation

> US National Institutes of Health, RePORTER application 9751401, MOLECULAR ANALYSIS OF HINDBRAIN DEVELOPMENT (5R01NS038183-21). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9751401. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*