# Genetic regulation of cardiac inflow tract formation in zebrafish

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $497,701

## Abstract

PROJECT SUMMARY
Organogenesis requires the execution of interwoven patterning processes that sculpt the distinct functional
components of an organ with exquisite specificity. In the context of the embryonic heart, specific territories
within each cardiac chamber take on unique attributes: for example, the pacemaker cells that reside within the
atrial inflow tract (IFT) have particular conductive properties that are integral to their role in initiating the
heartbeat. Cardiac pacemaking activity must be confined to a discrete region of the heart in order to avoid
arrhythmia, but we do not yet fully understand the genetic pathways that define the dimensions of the IFT.
How are an appropriate number of specialized cardiomyocytes established at the IFT? Prior studies have
shown that IFT progenitor cells inhabit discrete outlying regions of the anterior lateral plate mesoderm (ALPM).
Moreover, we have demonstrated that canonical Wnt signaling is active in these outlying regions and that the
ligand Wnt5b acts to drive IFT differentiation. Thus, Wnt signaling plays a key role in promoting IFT
development, but we do not yet understand how Wnt pathway activity is restricted to the edges of the ALPM.
Here, we propose to utilize the suite of genetic and embryological approaches available in the zebrafish in
order to identify essential patterning mechanisms that constrain IFT dimensions.
Importantly, our preliminary studies suggest that the number of IFT cardiomyocytes is constrained through a
two-phase process, with distinct signaling pathways operating at successive developmental stages. First, in
the early embryo, we propose that Hedgehog (Hh) signaling restricts the allocation of progenitor cells into the
IFT lineage. Later, in the ALPM, we propose that Fgf signaling reinforces constraints on the number of IFT
cardiomyocytes by restricting the distribution of Wnt signaling. Together, our preliminary data highlight
previously unappreciated roles for both Hh and Fgf signaling and suggest a novel model for the molecular
mechanisms that restrict the size of the IFT. To test this model, we will employ loss- and gain-of-function
analysis, fate mapping, and mosaic analysis in order to (1) determine whether Hedgehog signaling constrains
specification of IFT progenitor cells and (2) ascertain whether Fgf signaling constrains differentiation of IFT
cardiomyocytes. In addition, our model predicts that IFT progenitor cells possess distinct molecular
characteristics prior to their overt differentiation into IFT cardiomyocytes. To test this, we will (3) define the
developmental path of IFT progenitors by integrating spatial and transcriptomic data, thereby revealing how the
signaling pathways that specify the IFT lineage set the stage for differentiation of the IFT myocardium.
Taken together, our proposed studies will provide novel insight into the network of signaling pathways that
control IFT dimensions, thereby illuminating new paradigms for the regulation of cardia...

## Key facts

- **NIH application ID:** 10405548
- **Project number:** 5R01HL158112-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Neil C Chi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $497,701
- **Award type:** 5
- **Project period:** 2021-05-14 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405548

## Citation

> US National Institutes of Health, RePORTER application 10405548, Genetic regulation of cardiac inflow tract formation in zebrafish (5R01HL158112-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10405548. Licensed CC0.

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