Proper function of precisely wired neural circuits depends on a close physical and functional relationship with an equally complex and overlapping network of blood vessels. Blood vessels provide neurons with oxygen and nutrients and protect them from toxins and pathogens. Nerves, in turn, control blood vessel dilation and contraction and also heart rate. Key to this functional interdependence is an extraordinarily tight physical association between neurons and endothelial cells, with nearly every neuron in the human brain estimated to be supplied by its own capillary. Indeed, recent evidence suggests that neurodegenerative diseases once thought to be caused by intrinsic neuronal defects are in fact initiated and perpetuated by vascular abnormalities. However, despite the importance of this intimate relationship, how the nervous system becomes closely aligned with the vascular system during development and what molecular signals permit ongoing neurovascular interactions in the adult remains mystery. The goal of our research is to understand the molecular mechanisms of how neural and vascular networks are coordinately developed, communicated, and evolve to work in concert during normal and disease states. Investigating interactions between the vascular and nervous systems in essential for understanding nervous system function and also the underlying causes of neurological diseases.
Using a combination of mouse genetics, cell biology, biochemistry, and imaging techniques, our research program currently explores 5 topics:
- Uncover the molecular mechanisms underlying the neurovascular congruency during development.
- Characterize how common guidance cues and their receptors function in wiring neural circuitry and shaping up the vascular topology.
- Characterize the intriguing neurovascular anatomical relationship in the brain, including how neural activity changes vascular network.
- Identify novel factors from endothelial cells that control neuronal function and vice versa, including the factors control the blood brain barrier formation.
- Address how patterning cues influence human disease, involving both neural and vascular damage and repair.
To study these questions in vivo, we use genetically engineered mouse models with specific mutations and tracers combined with imaging and physiological approaches. To complement this work, we also perform studies in chick and a variety of in vitro assays to further reveal the mechanisms of action. With these approaches, we aim to understand the neurovascular interactions from a molecular level to a systems level.
An example of neurovascular congruency. An E11.5 mouse embryo was immunostained with anti-neurofilament (red) for spinal nerves and anti-PECAM (green) for intersomitic vessels. Our work revealed the molecular determinants and mechanisms that control the neurovascular congruency. In this case, intersomitic vessel and spinal nerve congruency does not result from vessels following nerves or nerves following vessels. Instead, it is achieved through a co-patterning mechanism by environmental cues secreted from the somite. Sema3E from the somite interacts with its receptor plexin-D1 in the endothelial cells to control intersomitic vessel patterning, while Sema3A and 3F in the somite interacts with neuropilin-1/2 to control spinal nerve projections. The coordinate interaction of both sets of ligands and receptors ensures congruency is established during development.
Establishment of neurovascular congruency in the mouse whisker system by an independent patterning mechanism. October 16, 2013. Neuron.
The role of semaphorins and their receptors in vascular development and cancer. February 17, 2013. Experimental cell research.
The role and mechanism-of-action of Sema3E and Plexin-D1 in vascular and neural development. December 25, 2012. Seminars in cell & developmental biology.
Neuroligin-1-dependent competition regulates cortical synaptogenesis and synapse number. November 11, 2012. Nature neuroscience.
Semaphorin 3E-Plexin-D1 signaling controls pathway-specific synapse formation in the striatum. December 18, 2011. Nature neuroscience.
Semaphorin 3E-Plexin-D1 signaling regulates VEGF function in developmental angiogenesis via a feedback mechanism. July 1, 2011. Genes & development.
VEGF mediates commissural axon chemoattraction through its receptor Flk1. June 9, 2011. Neuron.
Neuropilin 1-Sema signaling regulates crossing of cingulate pioneering axons during development of the corpus callosum. April 8, 2009. Cerebral cortex (New York, N.Y. : 1991).
Guidance from above: common cues direct distinct signaling outcomes in vascular and neural patterning. February 4, 2009. Trends in cell biology.
Distinct roles for secreted semaphorin signaling in spinal motor axon guidance. December 22, 2005. Neuron.
Guidance of trunk neural crest migration requires neuropilin 2/semaphorin 3F signaling. November 30, 2005. Development (Cambridge, England).
Peripheral nerve-derived VEGF promotes arterial differentiation via neuropilin 1-mediated positive feedback. January 26, 2005. Development (Cambridge, England).
Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. November 18, 2004. Science (New York, N.Y.).
Vascular endothelial growth factor controls neuronal migration and cooperates with Sema3A to pattern distinct compartments of the facial nerve. November 15, 2004. Genes & development.
Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. July 1, 2003. Developmental cell.
Characterization of neuropilin-1 structural features that confer binding to semaphorin 3A and vascular endothelial growth factor 165. March 8, 2002. The Journal of biological chemistry.
Apoptotic signaling through the beta -adrenergic receptor. A new Gs effector pathway. July 7, 2000. The Journal of biological chemistry.
p75 neurotrophin receptor as a modulator of survival and death decisions. May 1, 1999. Microscopy research and technique.
Oligodendrocyte apoptosis mediated by caspase activation. April 15, 1999. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Neurotrophins in cell survival/death decisions. January 1, 1999. Advances in experimental medicine and biology.
BRE: a modulator of TNF-alpha action. September 1, 1998. FASEB journal : official publication of the Federation of American Societies for Experimental Biology.
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