# MAB21L Family in Human Ocular Disease and Development

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $356,889

## Abstract

PROJECT SUMMARY/ABSTRACT
Coloboma is a congenital segmental ocular defect which can affect various structures of the eye.
Coloboma is often associated with microphthalmia, microcornea, and/or retinal detachment and leads to
visual impairment. We and another group recently reported a novel factor associated with coloboma,
MAB21L2. As part of these studies, we generated a zebrafish mab21l2 allelic series carrying frameshift,
in-frame indel and missense mutations in the orthologous gene region and observed coloboma and
severe ocular disorganization in these mutants. Next, screening of another MAB21L gene, MAB21L1, in
human patients identified likely pathogenic alleles indicating an independent role in human ocular disease.
We followed up this finding with the development of additional zebrafish lines carrying frameshift alleles in
the mab21l1 gene and identified coloboma and anterior segment defects in these mutants. These studies
revealed essential and conserved roles for MAB21L1/mab21l1 and MAB21L2/mab21l2 in ocular
development. The MAB21L factors encode proteins similar to C. elegans mab-21 cell fate-determining
factor; however, the function of these proteins is largely unknown. In this project, we will reveal MAB21L
function in ocular development. Our primary hypothesis is that MAB21L factors represent regulatory
proteins that, through interaction with PAX6 and the BMP signaling pathway, direct normal eye patterning.
This will be investigated through the following aims: 1) to uncover the cellular and molecular processes
controlled by MAB21L/mab21l factors during eye development and 2) to reveal the function of
MAB21L/mab21l proteins during eye development. The first aim will explore mab21l2 and mab21l1
mutants to identify disrupted cellular processes using various methods including time-lapse 4D
microscopy in collaboration with Dr. Kwan. To gain an insight into the mechanisms by which mab21l
factors direct ocular development, transcriptome and proteome analyses of mutants will be performed to
identify transcripts/proteins with significant deviation from normal patterns. The identified factors will be
further evaluated by rescue experiments in zebrafish mutants as well as sequencing of orthologous genes
in human patients. The second aim will focus on functional examination of MAB21L proteins using SELEX
and ChIP sequencing in a mab21l2-FLAG knock-in line. The obtained data will be analyzed together with
transcriptome/proteome data to reveal the hierarchy of molecular changes and define the underlying
mechanisms. The interaction between mab21l and pax6 factors, as well as mab21l and the bmp4
pathway, will be examined using corresponding mutant and reporter lines. The outlined experiments will
reveal novel mechanisms of vertebrate ocular development and human disease.

## Key facts

- **NIH application ID:** 9875463
- **Project number:** 5R01EY025718-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Elena V Semina
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $356,889
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875463

## Citation

> US National Institutes of Health, RePORTER application 9875463, MAB21L Family in Human Ocular Disease and Development (5R01EY025718-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9875463. Licensed CC0.

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