# Pax6 as a key regulator of lens development

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2021 · $534,691

## Abstract

The long-term goal of this program is to define the requirements for mammalian eye development by
elucidating the mechanisms employed by three DNA-binding transcription factors, including Pax6, Prox1,
and Gata3, in ocular lens morphogenesis. These factors form a regulatory network that controls key steps
of mammalian lens formation. This network is governed by multiple tissue-specific and developmentally
controlled enhancers regulated by BMP and FGF signaling through their signal-regulated transcription
factors (SRTFs) such as AP-1, Ets, and Smads. Pax6 regulates all essential steps of lens development
from the birth of lens progenitor cells, followed by the expansion and organization of the progenitor cells to
form the lens placode, reciprocal invagination of the lens placode with the optic vesicle to form the lens
vesicle and optic cup, and finally, the formation of posterior lens fibers and anterior lens epitelium that
constitute the mature ocular lens. To elicidate the molecular mechanisms underlying this intricate
developmental program, we employed unbiased genomic studies to generate a comprehensive map of
Pax6-determinate chromatin-regulatory landmarks that revealed novel lens-specific Pax6-bound 5'- and 3'-
distal enhancers of the Pax6 locus. We discovered that Pax6 directly regulates the actions of a second
critical lens transcription factor, Prox1, and that differentiation of primary lens fibers also requires
transcription factor Gata3. We also identified a lens-specific distal enhancer of the Gata3 locus that is
enriched for cis-motifs recognized by the BMP- and FGF-regulated SRTFs. Collectivelly, our new data
provide the basis for the central premise of this proposal: Pax6, Prox1, Gata3, and SRTFs orchestrate lens
development as integrators of BMP and FGF signaling, employ Pax6 autoregulation to maintain lens-cell
type, employ genetic cascade including Pax6 → Prox1 and SRTFs/Prox1 → Gata3 modules, and include
direct regulation of Cdk inhibitors of cell cycle progression, Cdkn1b/p27 and Cdkn1c/p57, by Gata3, Prox1,
and SRTFs. To reveal these regulatory mechanisms, we propose (1) To establish the molecular
mechanisms required for lens cell formation during early embryogenesis, and (2) To elucidate the molecular
mechanisms by which Pax6, Prox1, Gata3, and SRTFs control cell cycle exit-coupled differentiation of lens
cells. The proposed studies are supported by strong preliminary data identifying two novel lens-specific
Pax6 “super-enhancers”, requirements of BMP and FGF factors for lens induction, direct regulation of Prox1
by Pax6 via two novel enhancers, and disrupted lens differentiation from the stage of lens vesicle in Gata3
conditional lens mutants. These studies are expected to define for the first time those sequential events
required for the onset and propagation of Pax6 expression in the prospective lens ectoderm, identify
molecular phenotype of lens cells, and establish gene regulatory networks (GRN) regulating cell cycle exit...

## Key facts

- **NIH application ID:** 10158487
- **Project number:** 5R01EY012200-24
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Ales Cvekl
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $534,691
- **Award type:** 5
- **Project period:** 2000-01-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10158487

## Citation

> US National Institutes of Health, RePORTER application 10158487, Pax6 as a key regulator of lens development (5R01EY012200-24). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10158487. Licensed CC0.

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