Friday, May 30, 2025
5/30/2025
Revealing the mechanisms of neural-mediated cardiac proliferation in Ciona robusta - Project Summary/Abstract Regulation of cardiomyocyte division is required for proper heart development, and is implicated in congenital heart disease. Neural innervation of the heart regulates heart rate, which impacts cardiomyocyte proliferation. Furthermore, neurons release neuropeptides that are key factors in promoting cell proliferation. Recent evidence suggests neural innervation from the sympathetic and parasympathetic nervous system (extrinsic innervation) of the heart promotes cardiomyocyte proliferation in post-natal mice. Ciona robusta are a closely related chordate, which have documented conserved features such as neurons within the heart (intrinsic neurons). Unlike mammalian hearts that cease proliferating shortly after birth, Ciona hearts proliferate during development and into adulthood. The neurons associated with Ciona hearts are peptidergic, suggesting neuropeptides are secreted from these neurons. Tachykinin is a conserved family of neuropeptides that includes Substance P, which is implicated in cardiac disease, and is secreted from nerves that innervate the heart in vertebrates. The function of neural innervation in Ciona is not known, however we have preliminary data indicating the neuropeptide tachykinin promotes cardiac proliferation in the developing and adult Ciona heart. The sole article documenting Ciona heart innervation has not been followed up, and thus we investigated if there was unappreciated extrinsic innervation that exists in Ciona hearts. We find evidence of neurons from the brain (extrinsic) of Ciona innervating the intrinsic neurons of the heart. We hypothesize that neuronal input promotes proliferation in developing Ciona hearts. This hypothesis is supported by our preliminary data that the developing Ciona heart is innervated by extrinsic and intrinsic neurons. Furthermore, our data suggest tachykinin signaling promotes cardiac proliferation in developing and adult animals. Last, our preliminary single cell RNA-seq data suggest intrinsic neurons in the heart can respond to tachykinin. We propose the following aims to investigate our hypothesis. Aim I: Characterize neuronal innervation of the Ciona heart. We will determine the temporal and spatial time- course of neural innervation of the Ciona heart. We will use single cell RNA-seq to identify markers of all cell types in the heart including those expressing the tachykinin receptor (neurokinin) and subtypes of neurons. Aim II: Determine whether neuronal signaling regulates cardiac cell proliferation. We will identify the developmental time-point(s) which tachykinin activates cardiomyocyte proliferation. Next we will prevent tachykinin signaling in intrinsic neurons or cardiomyocytes to determine what cell type tachykinin acts on. We will investigate if tachykinin promotes cardiomyocyte proliferation indirectly by testing if the growth factors released by intrinsic neurons promote cardiomyocyte proliferation directly. My ultimate career goal is to study the role of neural innervation on cardiac development at a primarily undergraduate institution.
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