Molecular Mechanism of Brain Development and Differentiation

Abstract:
Structure of the Cerebellum is relatively simple since it contains only five types of neurons: main neuron is Purkinje cell and granule cells and other tyree types of neurons are all interneurons. Cerebellar circuitry is well understood down to the synaptic level. Cerebellum plays an important role in coordination of behaviour. Once there occurs abnormality, the animal shows typical cerebellar ataxia. We have been long working on the spontaneous mutant mice which show abnormality in behavior and morphogenesis. Studying the abnormally developed brain comparing with that of the normal animals gives us great information on the brain development. We identified high molecular weight protein, P400, deficient in Purkinje cells degeneration mutant mice. We discovered that P400 is an IP3 receptor and determined the whole sequence by cDNA cloning (Nature 1989). We found that IP3 receptor is a calcium ion channel involved in the release of free Ca2+ from intracellular stores. For analysis of the role of IP3-induced Ca2+ release (IICR) on patterning of the embryonic body, monoclonal antibodies that inhibit IICR were produced. Injection of these blocking antibodies into the ventral part of early Xenopus embryos induced modest dorsal differentiation. A close correlation between IICR blocking potencies and ectopic dorsal axis induction frequency suggests that an active IP3-Ca2+ signal may participate in the modulation of ventral differentiation (Science 1997b). IP3 receptor deficient mice showed cerebellar ataxia and epileptic seizure (Nature 1996).Long term depression of the cerebellum which is considered to be a memory mechanism in the cerebellum was suppressed in the IP3R1 deficient mice (J. Neurosci. 1998). We also found the importance of IP3 receptor in neurite extension by laser inactivation method (Science 1998a). Reeler mouse shows deranged neuronal positioning in the brain and is therefore important to analyse the molecular mechanism of neuronal positioning. We obtained monoclonal antibody (mAb) against reeler gene product (CR-50/reelin, Neuron 1995). This mAb blocks the cell positioning of the brain both in vivo and in vitro as well as neuronal process extension (Nature 1997a). Recently we found a spontaneous new mutant mice (yotari) which shows similar abnormality as reeler. We found mDab1 (mouse disabled) which is an adaptor protein of Src, Abl and Fyn tyrosine kinase is the responsible gene for the abnormality (Nature 1997b). We named Zic which is a zinc finger protein enriched in granule cells. Zic is a homologue of opa, pair rule gene that regulates neural induction (PNAS 1997). Knock out mouse of Zic1 showed abnormal cerebellar pattern formation (J.Neurosci. 1998). Zic2 gene is involved in brain induction and development. Zic3 is involved in left-right axis formation. It is interesting to know that the molecules and principles found in cerebellum could be applied to whole brain development, in general and even in body pattern formation.

Publications:     Nature 342, 32-38 (1989), Neuron 14, 899-912 (1995), Science 257, 251-255 (1992) Cell 73, 555-570 (1993), Nature 379, 168-171 (1996), PNAS 94, 8196-8201 (1997) Science 276, 1878-1882 (1997a), Science 278, 1940-1943 (1997b), Nature 385, 70-74 (1997a) Nature 389, 730-733 (1997b), J. Neurosci. 18, 284-293 (1998), Science 279, 237-242 (1998a) Science 282, 1705-1708(1998b)