# Investigation of fmnl2 in cerebellar development

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $39,957

## Abstract

PROJECT SUMMARY
Congenital ataxias generally result from dysfunctions and malformations of the cerebellum, particularly the
medial vermis. These disorders may result from the lack of proper developmental signaling cascades which
dictate the proliferation and formation of neurons. Primary cilia provide a hub for various developmental signaling
proteins such as SHH or WNT. Dysfunction in ciliary proteins leads to rare genetic disorders affecting human
development in the nervous system, optical system, and liver, kidney, and skeletal systems. Patients with
ciliopathies like Joubert Syndrome and related disorders display cerebellar vermis hypoplasia, thickened superior
cerebellar peduncles, and a deepened interpeduncular fossa. Components of the cytoskeleton, such as actin
and microtubules, play a vital role in ciliogenesis and the maintenance of existing ciliary components and
supporting scaffold. Although many cilia-related genes have been found to be causal for these disorders,
cytoskeletal regulators of the formin family and their relationship with cilia has not yet been fully defined, nor
have these molecules been previously associated with abnormal brain development.
Our lab uses a forward genetic approach to identify pathways critical to cerebellar development and degeneration
of neurons in this brain region. Through a chemical mutagenesis screening, we discovered an ataxic mouse
mutant with phenotypes similar to those observed in some ciliopathies: cerebellar hippocampal hypoplasia,
abnormal foliation, cerebellar elongation along the anterior-posterior axis, as well as the failure of the superior
cerebellar peduncle to decussate. By positional cloning, we identified a mutation at a splice acceptor in Fmnl2,
leading to exon skipping in Fmnl2 transcripts. Interestingly, levels of Fmnl2 transcripts in the brain of mutant mice
are unchanged compared to WT, but protein levels are reduced, suggesting that the in-frame deletion encoded
by this exon are necessary for stability of this protein.
FMNL2 is an autoinhibited cytoskeletal effector that has been previously shown to drive actin polymerization at
filopodia and lamellipodia tips of cultured cells. Although other proteins in this family have shown to bind and
regulate microtubules, actin, and influence cilia formation, whether this protein functions in microtubules and
actin during brain development is unknown. Using this novel mouse model, I will investigate the role of FMNL2
in actin and microtubule stabilization and determine how the hypomorphic loss of this protein may impact
ciliogenesis and cilia maintenance. These studies will enlighten our understanding of cerebellar malformations
and impact our understanding of the mechanisms underlying the role of microtubules and actin in human
ciliopathies.

## Key facts

- **NIH application ID:** 10466624
- **Project number:** 1F30HD108986-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Joyce Tran
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,957
- **Award type:** 1
- **Project period:** 2022-06-02 → 2026-06-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466624

## Citation

> US National Institutes of Health, RePORTER application 10466624, Investigation of fmnl2 in cerebellar development (1F30HD108986-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10466624. Licensed CC0.

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