This project is to determine the molecular basis of how sympathetic nerves extend axons along the vasculature with the goal of innervating their target organs. To study this, we use the coronary vasculature model as a favorable model system. We discovered a reciprocal guidance event in the patterning of sympathetic nerves in the developing heart. Our whole-mount imaging revealed that the pattern of large-diameter coronary veins influences the pattern of sympathetic innervation in the heart. Further genetic studies and in vitro organ culture experiments demonstrated that coronary veins serve as an intermediate template that guides distal sympathetic axon projection via local secretion of NGF by coronary vascular smooth muscle cells (Nam et al. 2013). This coordinated process ultimately allows topological targeting of axons to final targets such as coronary arteries and the cardiac conduction system. Our results suggest that target organs possess unique and stereotypical patterns of innervation, mediated by tissue substructures, such as coronary veins in the heart, that are adapted to complex organ structure and physiology. We are currently exploring the regulatory mechanisms by which coronary VSMCs guide patterns of sympathetic innervation and tackle two intriguing unresolved questions in neuronal development: how does guidance factor expression shift from central to peripheral blood vessels (e.g. from subepicaridial veins to myocardial arteries) in parallel with axon extension along these vessels;what determines the choice of either innervation to blood vessels or axon extension along blood vessels en route to their final targets. These studies will provide a molecular mechanistic framework for the developmental program underlying vascular control of neuronal guidance and innervation patterns.
| Sandeep, Nefthi; Uchida, Yutaka; Ratnayaka, Kanishka et al. (2016) Characterizing the angiogenic activity of patients with single ventricle physiology and aortopulmonary collateral vessels. J Thorac Cardiovasc Surg 151:1126-35.e2 |
| Liu, Zhihui; Li, Wenling; Ma, Xuefei et al. (2014) Essential role of the zinc finger transcription factor Casz1 for mammalian cardiac morphogenesis and development. J Biol Chem 289:29801-16 |
| Mukouyama, Yoh-suke (2014) Vessel-dependent recruitment of sympathetic axons: looking for innervation in all the right places. J Clin Invest 124:2855-7 |
| Nam, Joseph; Onitsuka, Izumi; Hatch, John et al. (2013) Coronary veins determine the pattern of sympathetic innervation in the developing heart. Development 140:1475-85 |
| Mukouyama, Yoh-suke; James, Jennifer; Nam, Joseph et al. (2012) Whole-mount confocal microscopy for vascular branching morphogenesis. Methods Mol Biol 843:69-78 |
