The normal function of the brain relies on precise patterns of neuronal connections, and aberrant connectivity leads to human neurological and psychiatric disorders. The human brain consists of approximately100 billion neurons with trillions of synapses. Because of the enormous neuronal diversity and staggering synaptic complexity, very little is known about the molecular mechanisms that lead to the assembly of specific synapses in different neuronal types. Protocadherin (Pcdh) genes (14 Pcdh-a, 22 Pcdh-fi and 22 Pcdh-y in mouse) are attractive candidates for such a role because they can potentially generate a significant number of cell-surface """"""""codes"""""""" through a combination of cell-specific promoter activation andcis- alternative splicing. It has been suggested that the distinct combinatorial Pcdh expression patterns might specify neuronal types and their connectivity. To evaluate their roles in neural development, we initiated functional analyses of these genes using genetically modified mice. Our analyses on Pcdh-j mutant mice provide the first in vivo evidence that protocadherins are essential for vertebrate CNS development and play an important role in establishing neuronal connectivity. However, Pcdh-y's function during synaptic development is not well defined and its molecular mechanisms of action are completely unknown. We plan to combine molecular and genetic approaches to further our understandingof Pcdh-y's functions.Specifically, we propose 1) to investigate the rules of expression for individual isoforms of Pcdh-y;2) to define the role of Pcdh-y's diversity;and 3) to identify and characterize the signaling components of Pcdh-y. The attainment of these goals will shed light on our understandingof the molecular basis for the precision and complexity of neuronal circuitry in the brain.
| Su, Hong; Marcheva, Biliana; Meng, Shuxia et al. (2010) Gamma-protocadherins regulate the functional integrity of hypothalamic feeding circuitry in mice. Dev Biol 339:38-50 |
| Lin, Chengyi; Meng, Shuxia; Zhu, Tina et al. (2010) PDCD10/CCM3 acts downstream of {gamma}-protocadherins to regulate neuronal survival. J Biol Chem 285:41675-85 |
| Han, Meng-Hsuan; Lin, Chengyi; Meng, Shuxia et al. (2010) Proteomics analysis reveals overlapping functions of clustered protocadherins. Mol Cell Proteomics 9:71-83 |
| Chen, Jian; Lu, Yanyan; Meng, Shuxia et al. (2009) alpha- and gamma-Protocadherins negatively regulate PYK2. J Biol Chem 284:2880-90 |
| Lu, Yanyan; Lin, Chengyi; Wang, Xiaozhong (2009) PiggyBac transgenic strategies in the developing chicken spinal cord. Nucleic Acids Res 37:e141 |
