# Deciphering the Role of Frizzled Receptors in Palatal Development

> **NIH NIH K08** · VAN ANDEL RESEARCH INSTITUTE · 2022 · $109,274

## Abstract

PROJECT SUMMARY/ABSTRACT
Cleft lip and/or cleft palate has an incidence of approximately 1 in 700 births making it one of the most common
congenital birth defects. Gaining a more complete understanding of the genetics and signaling mechanisms
involved will provide a foundation for improving treatment of patients with orofacial clefts, ultimately reducing
an enormous burden on the healthcare system. Several signaling pathways intersect to regulate the proper
development of the palate which makes developing targeted therapies to treat or prevent cleft palate
challenging. Dissecting the components of each pathway involved will provide a more complete picture of
palatogenesis. The Wnt signaling pathway is an important regulator of palatal development and regulates early
patterning by cranial neural crest cells through regulation of induction, migration, and differentiation of these
cells. Wnt signaling also intersects many morphogenic pathways that regulate palatal shelf elongation,
elevation, and fusion. Frizzleds (FZDs) are transmembrane receptors for Wnt ligands and mutations in some of
the 10 FZD genes have been identified in patients with both syndromic and non-syndromic cleft lip and/or
palate. Specifically, heterozygous nonsense mutations in FZD2 have been identified in patient families with
Robinow Syndrome (RS) or Autosomal Dominant Omodysplasia (ADO), syndromes which are characterized
by limb reductions and craniofacial anomalies including cleft palate. While these mutations in FZD2 were
thought to cause haploinsufficiency, heterozygous deletion of Fzd2 in mice does not lead to cleft palate. We
will use mouse models harboring RS/ADO-associated mutations to better understand how FZD2 functions in
the developing palate. Given the association of mutations in other Wnt pathway genes (WNT5A, ROR2, DVL)
in RS and ADO, we hypothesize that these components signal together with FZD2 to regulate palatogenesis.
We hypothesize that FZD2 regulates cell migration and palatal patterning through a non-canonical WNT5A-
ROR2 pathway and further hypothesize that human RS- and ADO-associated Fzd2 mutations act dominantly
to interfere with Fzd signaling. To achieve these research goals, we propose the following aims: 1) determine
the phenotypic consequences of Fzd2 deletion and RS/ADO-Fzd2 mutations on palatal development in mice,
and 2) determine the molecular mechanisms behind Fzd2 regulation of palate development. Data generated in
this proposal will ultimately support the development of novel therapeutic approaches and interventions in Wnt
signaling-related diseases. These research plan and career development activities proposed here will form a
solid basis for my future independent research program.

## Key facts

- **NIH application ID:** 10454367
- **Project number:** 5K08DE031039-02
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Megan Michalski
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $109,274
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454367

## Citation

> US National Institutes of Health, RePORTER application 10454367, Deciphering the Role of Frizzled Receptors in Palatal Development (5K08DE031039-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10454367. Licensed CC0.

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