The mechanisms of trabecular morphogenesis and myocardial proliferation are clinically important but poorly understood. Understanding these mechanisms is the key to identifying the etiology of left ventricular noncompaction (LVNC) and successfully regenerating myocardium after cardiac damage, respectively. LVNC is a form of cardiomyopathy characterized by failure of the trabeculae to undergo compaction. Lack of trabeculation causes embryonic lethality, while excess or persistent trabeculation causes cardiomyopathy and heart failure. The Notch1 signaling pathway is well known to regulate trabeculation and myocardial proliferation. However, the upstream components that modulate Notch1 signaling during trabeculation in mammals are not clear. Previously, by applying single-cell lineage tracing, we found that oriented cell division (OCD) and asymmetric cell division (ACD), a division with asymmetric distribution of cell fate determinants to two daughter cells, contribute to trabecular formation and specification in mice, respectively. However, the molecular mechanisms that control the mitotic spindle orientation of OCD and ACD during trabeculation are unknown. In our preliminary study, the deletion of Cdc42, a gene encoding a small GTPase that is required to establish cell polarity, in myocardium displayed an absence of trabeculation, abnormal cardiomyocyte specification, reduced Notch1 activation and reduced cardiomyocyte proliferation. We hypothesize that CDC42 regulates trabecular morphogenesis and specification by controlling cardiomyocyte OCD and ACD, and regulates cardiomyocyte proliferation by activating Notch1 signaling. We will Determine whether CDC42 regulates trabecular formation by controlling mitotic spindle orientation via genetic and cell biology approaches. We design experiments to test the hypothesis that CDC42 activates Notch1 signaling via controlling the trafficking of Jag1 to cardiomyocyte membrane. Completion of these aims will yield novel insights into cellular and molecular mechanisms of trabeculation and myocardial proliferation. This could ultimately provide a mechanistic basis for treating LVNC and identified potential targets for regenerative therapies for myocardial repair.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2019 → 12/31/2020|