Jay, P. Y. | Search bioRxiv

bioRxiv2023

Tiered Sympathetic Control of Cardiac Function Revealed by Viral Tracing and Single Cell Transcriptome Profiling

The cell bodies of postganglionic sympathetic neurons innervating the heart primarily reside in the stellate ganglion (SG), alongside neurons innervating other organs and tissues. Whether cardiac-innervating stellate ganglionic neurons (SGNs) exhibit diversity and distinction from those innervating other tissues is not known. To identify and resolve the transcriptomic profiles of SGNs innervating the heart we leveraged retrograde tracing techniques using adeno-associated virus (AAV) expressing fluorescent proteins (GFP or Td-tomato) with single cell RNA sequencing. We investigated electrophysiologic, morphologic, and physiologic roles for subsets of cardiac-specific neurons and found that three of five adrenergic SGN subtypes innervate the heart. These three subtypes stratify into two subpopulations; high (NA1a) and low (NA1b and NA1c) Npy-expressing cells, exhibit distinct morphological, neurochemical, and electrophysiologic characteristics. In physiologic studies in transgenic mouse models modulating NPY signaling, we identified differential control of cardiac responses by these two subpopulations to high and low stress states. These findings provide novel insights into the unique properties of neurons responsible for cardiac sympathetic regulation, with implications for novel strategies to target specific neuronal subtypes for sympathetic blockade in cardiac disease.

neuroscience↗

bioRxiv2019

The fitness cost of a congenital heart defect shapes its genetic architecture

BackgroundIn newborns, severe congenital heart defects are rarer than mild ones. The reason why is unknown, but presumably related to a liability threshold that rises with the severity of a defect. Because the same genetic mutation can cause different defects, other variables may contribute to pushing an individual past a defect-specific liability threshold. We consider here how variables in the genetic architecture of a heart defect depend upon its fitness cost, as defined by the likelihood of survival to reproductive age in natural history studies. MethodsWe phenotyped ~10,000 Nkx2-5+/- newborn mice, a model of human congenital heart disease, from two inbred strain crosses. Genome-wide association analyses detected loci that modify the risk of an atrial septal defect, membranous or muscular ventricular septal defect, or atrioventricular septal defect. The number of loci, heritability and quantitative effects on risk of pairwise (GxGNkx) and higher-order (GxGxGNkx) epistasis between the loci and Nkx2-5 mutation were examined as a function of the fitness cost of a defect. ResultsNkx2-5+/- mice have pleiotropic heart defects; about 70% have normal hearts. The model recapitulates the epidemiological relationship between the severity and incidence of a heart defect. Neither the number of modifier loci nor heritability depends upon the severity of a defect, but GxGNkx and GxGxGNkx effects on risk do. Interestingly, GxGxGNkx effects are three times more likely to suppress risk when the genotypes at the first two loci are homozygous and from the same, rather than opposite strains in a cross. Syn- and anti-homozygous genotypes at GxGxGNkx interactions can have an especially large impact on the risk of an atrioventricular septal defect. ConclusionsGiven a modestly penetrant mutation, epistasis contributes more to the risk of severe than mild congenital heart defect. Conversely, genetic compatibility between interacting genes, as indicated by the protective effects of syn-homozygosity at GxGxGNkx interactions, plays a newfound role in the robustness of cardiac development. The experimental model offers practical insights into the nature of genetic risk in congenital heart disease. The results more fundamentally address a longstanding question regarding how mutational robustness could arise from natural selection.

genetics↗