Yosuke Mukoyama, Ph.D.

Branching morphogenesis is a fundamental attribute of many organ systems. The laboratory of Dr. Yosuke Mukoyama (Yoh-suke Mukouyama in PubMed) aims to uncover the molecular control of the morphologic processes underlying the patterning of tubular branching networks, particularly the vascular and nervous systems, which share several anatomic and functional characteristics and are often patterned similarly in peripheral tissues. These characteristics suggest that these two networks are interdependent during tissue development and homeostasis. Thus, Dr. Mukoyama is studying neuronal influences on vascular branching patterns and vascular influences on both neuronal guidance and neural stem cell maintenance. His laboratory approaches these problems using a combination of high-resolution whole-mount imaging, molecular manipulations, advanced genetic perturbations, next-generation sequencing, and in vitro organ culture techniques.

By developing a model system of skin vasculature that allows for the direct observation of congruent vascular and neural networks in an anatomically recognizable pattern, Dr. Mukoyama and his colleagues have begun to unravel the neural control of vascular development. The CXCL12–CXCR4 and VEGF-A–VEGFR2/Nrp1 signaling pathways are important for sensory nerve-mediated arterial branching, while NGF–TrkA signaling is essential for guiding sympathetic axons along blood vessels. Using high-resolution whole-mount imaging in vivo Ca2+ indicator mice, they are currently examining how sensory activity changes in mutants with neurovascular mispatterning in developmental and pathological contexts, including obesity-related nerve disorders. These studies will provide novel conceptual advances in the development and maintenance of functional neurovascular wiring.

Just as nerves influence vascular patterns in the skin, Dr. Mukoyama and his colleagues have also shown that blood vessels influence nerve patterns in the developing heart. Using whole-mount imaging, they demonstrated that sympathetic axons branch alongside large-diameter coronary veins in the sub-epicardial layer of the dorsal ventricular wall before innervating final targets such as coronary arteries and cardiomyocytes in the deeper myocardial layer. This novel neurovascular association is established by sequential expression of NGF in the subepicardial venous vascular smooth muscle cells (VSMCs) and myocardial arterial VSMCs of coronary vessels. Using ultra-high-frequency non-invasive imaging, they found abnormal cardiac functions, such as irregular cardiac rhythms, in mutant embryos lacking the autonomic nervous system. Using 2D co-culture, 3D organoids and assembloids, and advanced imaging, they are currently examining what happens to myocardial development and conduction system architecture in the absence of the autonomic nervous system and how autonomic nerves affect cardiomyocyte differentiation and maturation. These studies will provide a mechanistic framework for the functional consequences of sympathetic innervation in the developing heart.

No examination of neurovascular interactions could neglect the brain. The vasculature component of this specialized niche microenvironment helps to retain neural stem cell potential, while the CNS parenchyma develops a blood-brain barrier (BBB) and lacks a lymphatic system. Dr. Mukoyama and his colleagues have also found BBB disruption and abnormal expression of the lymphatic endothelial transcription factor Prox1 in tumor-associated endothelial cells in glioma and metastatic tumors. Ongoing work investigates the relationship between ectopic Prox1 expression and BBB dysfunction.

These three independent but thematically interrelated projects provide unique opportunities to advance understanding of the dynamic features of both vascular and neuronal branching networks.

Yoh-suke Mukouyama, whose legal name is Yosuke Mukoyama, publishes as Yoh-suke Mukouyama. He received his A.B. in pharmacy studies from Tokyo University of Science and his M.S. and Ph.D. in developmental biology from the University of Tokyo. As a student in the laboratory of Dr. Atsushi Miyajima, he studied the properties of embryonic endothelial cells and hematopoietic stem cells (HSCs). He did postdoctoral research in the laboratory of Dr. David Anderson at the California Institute of Technology where he demonstrated that peripheral nerves direct arterial organization and formation by secreting VEGF; he also studied the properties of neural stem cells (NSCs). He joined the NHLBI as a tenure-track Investigator in 2006. He also serves on the editorial board of Developmental Dynamics and is a member of the North American Vascular Biology Organization.