# Roles for uniquely human enhancers in brain development and WNT signaling

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $694,047

## Abstract

ABSTRACT
Humans diverge from other primates in numerous ways including their neuroanatomy and cognitive capacities.
Human-specific features are particularly prominent in the cerebral cortex, which has undergone an expansion in
size and acquired unique cellular composition and circuitry. Many of these features arose through modifications
to cortical development, explained by human-specific gene expression. However, how human-specific gene
expression explains divergent brain development is poorly understood. This proposal aims to fill that gap by
investigating how non-coding regulatory loci impact human-specific brain development. Specifically, we focus on
human accelerated regions (HARs), which are ultra-conserved sequences which have rapidly acquired
mutations in the human lineage. HARs frequently physically associate with neurodevelopmental genes, and at
least 50% of HARs have enhancer activity in human neural cells. Further, HARs are broadly associated with
neurological disorders. Yet, biological functions for HARs in brain development remain largely unknown.
Our group discovered HARE5, which shows divergent human-chimpanzee (Hs-Pt) enhancer activity in the
developing mouse brain, due to just 4 mutations over 600 conserved nucleotides. HARE5 activates expression
of Fzd8, a receptor in the WNT signaling pathway which is implicated in brain size and neurological disease. We
have generated humanized HARE5 mouse models which exhibit expanded progenitor and neuron number and
enlarged brains. We have additionally discovered new HARs, which like HARE5, are predicted to impact WNT
signaling. This proposal will test the central hypothesis that evolutionary modifications of HAR enhancer
activity modulate WNT signaling to control neural progenitor dynamics in the developing brain. Our
proposal leverages our expertise and unique genetic tools, including mouse models, and human and non-human
primate iPSCs and organoids. We will investigate mechanisms of HARE5 function in mouse models (Aim 1) and
in cortical organoids generated from human and non-human primate iPSCs (Aim 2). We will then test roles for
12 WNT-associated HARs in neurogenesis (aim 3). Upon completion of this study, we will gain valuable insights
into the developmental underpinnings of human cognitive capacities which can inform the basis for
neuropsychiatric diseases.

## Key facts

- **NIH application ID:** 10806145
- **Project number:** 5R01MH132089-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Debra L. Silver
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $694,047
- **Award type:** 5
- **Project period:** 2023-03-09 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10806145

## Citation

> US National Institutes of Health, RePORTER application 10806145, Roles for uniquely human enhancers in brain development and WNT signaling (5R01MH132089-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10806145. Licensed CC0.

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