Date of Award

2026

Embargo Period

2-19-2028

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Regenerative Medicine and Cell Biology

College

College of Graduate Studies

Additional College

College of Medicine

First Advisor

Russell Norris

Second Advisor

Andy Wessels

Third Advisor

Antonis Kourtidis

Fourth Advisor

Neil Chi

Fifth Advisor

Donald Menick

Abstract

The mechanisms that govern cardiac morphogenesis also influence how it fails in disease, yet the underlying molecular, pathophysiological mechanisms linking these processes remain incompletely understood and constrain therapeutic progress. Murine models provide a powerful experimental platform to define these mechanisms and translate genetic and environmental risk into biological insight. This dissertation employs complementary mouse models and integrated approaches—including histology, westerns, transcriptomics, and digital pathology—to investigate how developmental signaling pathways regulate tissue organization and how postnatal disease processes remodel the heart.

The primary focus of this work is Dachsous cadherin-related 1 (DCHS1), an atypical cadherin implicated in planar cell polarity and Hippo signaling. Leveraging a hemagglutinin-tagged Dchs1 knock-in mouse, this dissertation defines the spatiotemporal expression of Dchs1 during cardiac development, revealing a predominantly fetal, non-cardiomyocyte pattern localized to endothelial and fibroblast populations. DCHS1-positive cells exhibit coordinated migration and homotypic and heterotypic cell–cell interactions, suggesting a role for DCHS1 in myocardial patterning.

Functional studies in Dchs1 knockout mice revealed abnormal cardiomyocyte proliferation despite the absence of Dchs1 expression in cardiomyocytes, supporting a non–cell-autonomous mechanism of cardiac growth regulation. A developmentally regulated, density-dependent, and metalloproteinase-sensitive proteolytic cleavage of DCHS1 was identified, separating its extracellular and intracellular domains. Guided by these findings, a novel Dchs1DICD-V5 murine model was generated. Deletion of the intracellular domain (ICD) recapitulated cardiomyocyte proliferative and valvular phenotypes, establishing the ICD as an essential signaling component of cardiac development.

Extracardiac analyses of Dchs1DICD-V5/DICD-V5 mice further revealed craniofacial, skeletal, and neurodevelopmental abnormalities that phenocopy Van Maldergem syndrome, implicating a previously unrecognized role for the DCHS1 ICD in DCHS1–FAT4–Hippo signaling.

This work also includes a global collaboration focused on rheumatic heart disease (RHD). We demonstrated Strep. pyogenes cell wall exposed, humanized mice recapitulate key features of human disease: including valvular dysfunction, inflammation, and fibrosis. This established the first mouse model for RHD, enabling studies of disease progression and therapeutic mechanisms.

Together, these studies trace a path from gene to phenotype, revealing how DCHS1-dependent signaling governs multisystem development and how immune-mediated injury remodels the heart, thereby advancing mechanistic frameworks for both developmental and acquired cardiovascular disease.

Rights

Copyright is held by the author. All rights reserved.

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Available for download on Saturday, February 19, 2028

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