# Nphp4 and Bbs5 are required for ciliary mediated cell signaling events that regulate cardiac development in the mouse

> **NIH NIH F31** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $19,916

## Abstract

Project Abstract: ( 30 lines maximum)
The primary cilium is a microtubule-based structure that protrudes from the surface of nearly every cell type in
the mammalian body. At the base of the cilium is a complex of proteins forming the transition zone (TZ), a
diffusion barrier separating the cilium from the cytoplasm. Correct separation of these domains is important for
establishing the cilium as a specialized sensory and signaling compartment. How proteins are transported into
and out of the cilium across the TZ is poorly understood but appears to involve a complex of eight proteins that
constitute the BBSome. Mutations disrupting these structures, and others related to primary cilia result in a
spectrum of human diseases collectively called ciliopathies. These disruptions manifest in a plethora of
physiological and developmental disorders that are highly variable. The primary goals of my study are to
elucidate the mechanism by which the TZ and BBSome collaboratively work to regulate primary cilium
functions important for normal cardiac development in mice, and to elucidate ciliary related regulation of
Congenital Heart Defects (CHD). In the United States, CHD is the leading cause of birth-defect associated
illness and death in infants. Studies from a genetic screen orchestrated to identify CHD-related genes identified
34 that were associated with the cilium out of 61 total CHD associated genes. Furthermore, studies that have
specifically removed the primary cilium from the developing heart have reported CHD related abnormalities.
These data strongly support the premise of this application that the primary cilium plays an extensive, but not
yet understood, role in CHD pathogenesis. We have previously identified identified genetic interactions
between the TZ component, Nphp4, and the BBSome component, Bbs5, through studies in C. elegans. The
goal of my study is to extend these studies into a mammalian system and to define the contribution that Nphp4
and Bbs5 have during heart development. My preliminary data indicate that Nphp4; Bbs5 double mutant mice
are embryonic lethal between embryonic day 16.5 and birth, while each of the single mutants is viable. My
preliminary studies indicate that the lethality is likely associated with critical events disrupting cardiac
development. Based on my preliminary data, I hypothesize that genetic interactions between Nphp4 and Bbs5
are necessary for proper cilia function and cardiovascular development, likely through altered regulation of
transport of proteins into and out of the cilium. Thus, the data generated from this study will provide critical new
understanding of how the primary cilium regulates early cardiac development and how cilia dysfunction
contributes to CHD.

## Key facts

- **NIH application ID:** 10116177
- **Project number:** 5F31HL150898-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Melissa R Bentley
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $19,916
- **Award type:** 5
- **Project period:** 2020-03-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116177

## Citation

> US National Institutes of Health, RePORTER application 10116177, Nphp4 and Bbs5 are required for ciliary mediated cell signaling events that regulate cardiac development in the mouse (5F31HL150898-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10116177. Licensed CC0.

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