The Role of Kinases Signaling in Organogenesis

Author

Fatemeh NasehiFollow

Date of Award

8-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Bioengineering

Committee Chair/Advisor

Ann C Foley

Committee Member

Dan Simionescu

Committee Member

Yongren Wu

Committee Member

Robin C. Muise-Helmericks

Abstract

Kinases are crucial regulators of organ development and differentiation. This thesis investi- gates the roles of TAK1, TGFbeta-Activate Kinase 1 (TAK1/Map3K7), and Akt3 kinases in skeletal, cardiac muscle, and cartilage. TAK1 is pivotal for the differentiation of various organ systems, including sinoatrial node and cartilage, and is responsible for phosphorylat- ing a diverse array of downstream kinases. We identified several novel proteins, including phospho-Akts, that are upregulated in response to TAK1 activation. We discovered severe Dilated Cardiomyopathy (DCM) and cartilage defects in Akt3 mutant mice. Although this mouse mutant has been studied for over two decades, we are the first to identify these defects. The molecular mechanisms and underlying genetics of both DCM and cartilage defects are poorly understood. Akt3 is implicated in various cellular processes that could contribute to DCM and cartilage defects, including mitochondrial biogenesis and mitosis. This thesis addresses how these functions might account for the underlying disease phenotypes observed in Akt3 mutant mice.

I have evaluated Akt3 mutant hearts at various stages, finding that embryonic hearts are smaller than their age-matched wild types, a condition correlated with decreased cell pro- liferation and increased cell death. By ten weeks after birth, these mutant hearts exhibit severe dilation and an increased overall size. Additionally, increased fibrosis, more collagen deposition, and numerous vascular anomalies have been observed.

Juvenile Akt3 mutant mice also exhibit decreased cartilage, reduced chondrocyte viability, and increased fragility of the cartilage. Together, these findings make Akt3 mutant mice anexcellent model for studying the etiology of severe DCM and cartilage defects. The exact mechanism by which the loss of Akt3 leads to DCM and cartilage defects is unknown. Our published data demonstrate that in the absence of Akt3, CRM1 and Lamin A/C are upregu- lated, resulting in disruptions in mitosis, micronuclei formation, and loss of nuclear envelope integrity. Lamin A/C protein expression is closely correlated with biomechanical stiffness. Our hypothesis proposes that Akt3 plays a critical role in the development of DCM and cartilage defects through Lamin A/C regulation. This thesis explores the regulatory roles of Akt3 on Lamin A/C and biomechanical stiffness in both DCM and cartilage development.

Recommended Citation

Nasehi, Fatemeh, "The Role of Kinases Signaling in Organogenesis" (2024). All Dissertations. 3683.
https://open.clemson.edu/all_dissertations/3683

Author ORCID Identifier

0000-0003-3662-749X