Date of Award

Spring 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics

First Advisor

Khokha, Mustafa

Abstract

Congenital Heart Disease (CHD) is the most common birth defect and leading cause of infant mortality, yet molecular mechanisms explaining CHD remain mostly unknown. Sequencing studies are identifying CHD candidate genes at a brisk rate including MINK1, a serine/threonine kinase. However, a plausible molecular mechanism connecting CHD and MINK1 is unknown. Here, we reveal that mink1 is required for proper heart development due to its role in left-right patterning. Mink1 regulates canonical Wnt signaling to define the cell fates of the Spemann organizer and the Left-Right Organizer, a ciliated structure that breaks bilateral symmetry in the vertebrate embryo. To identify Mink1 targets, we applied an unbiased proteomics approach and identified the high mobility group architectural transcription factor, Hmga2. We report that Hmga2 is necessary and sufficient for specifying Spemann’s Organizer. Indeed, we demonstrate that Hmga2 can induce Spemann Organizer cell fates even when Beta-catenin, a critical effector of the Wnt signaling pathway, is depleted. Finally, we describe a role for mink1 in specification of the Xenopus embryonic multiciliated epithelium, potentially indicating a risk for mucociliary clearance defects in CHD patients with MINK1 variants. In summary, we discover a transcription factor, Hmga2, downstream of Mink1 and Beta-catenin that is critical for the specification of Spemann’s Organizer, as well as the LRO defining a plausible mechanism for CHD. We also unearth an important potential avenue for postoperative treatment of CHD patients.

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