Takeshi Sakurai, MD, PhD

My research interest has been how nervous system forms its structure and establishes stereotyped and precise connections. For this, I have been studying neuronal cell adhesion molecules (CAMs), in particular, the L1 family of neuronal CAMs. The biological relevance of these CAMs in nervous system development is underscored by the fact that in humans, mutations in the L1 gene cause the CRASH syndrome, congenital brain defects including axon misguidance. Moreover, mutations in ChL1, another family member, have shown to be responsible for a certain form of mental retardation and schizophrenia, resulted from morphological changes in the brain. For last 6 years, I have analyzed biological function of one of the L1 family CAMs, Nr-CAM, in development of the visual system and cerebellum by using several in vitro culture systems as well as in vivo analyses involving gene targeting and transgenic mice. Our study suggests that Nr-CAM is important for cerebellar granule cell axon growt h. Moreover, Nr-CAM is involved in formation of partial decussation at the optic chiasm, structural basis of binocular vision in mammals. Nr-CAM is also important for formation of the node of Ranvier in myelinated nerves. These results support that Nr-CAM plays crucial roles in several aspects of nervous system development.

Currently, using in vitro cultures as well as in vivo analyses, we are further analyzing function of Nr-CAM in development of nervous system, especially focusing on its function in retinal axon guidance, its mode of action and relationship with other guidance mechanisms involved in optic chiasm formation at the molecular level. This study should provide us with insight into how precise wiring in the brain, structural basis of neuronal function, occurs during development. In nerve regeneration, restoration of appropriate wiring is crucial and understanding of this process at the molecular level is important when we intend to achieve effective functional recovery from brain/spinal cord injury.

Alterations in molecules involved in nervous system development affect brain structure and function, resulting in neurological and psychiatric disorders. The latter includes autism and schizophrenia, both of which have been shown to be developmental disorders. We found that variations in the Nr-CAM gene in humans are associated with autism with severe obsessive compulsive behavior as well as substance abuse vulnerability. Our hypothesis is that Nr-CAM is involved in formation of particular nerve circuitry in the brain whose alterations are responsible for these behavioral aspects, and by using mouse models, we are trying to clarify if this is true. In addition to these CAMs, we are characterizing function of several genes in nervous system development that have been shown to be associated with autism and schizophrenia, using in vitro cultures as well as in vivo analyses with model mice. By understanding function of the molecules involved in nervous system development and pos sible outcomes caused by alterations of those molecules, we hope to gain insight into pathogenesis of these disorders in order to ultimately devise effective therapeutic approaches.