Dissecting functions of Shp2 tyrosine phosphatase in the central nervous system.

摘要

Shp2 functions as a cytoplasmic protein tyrosine phosphatase in multiple fundamental cellular signaling pathways to regulate basic mechanisms such as proliferation, differentiation, apoptosis, and motility. Notably, two genetic disorders in humans, Noonan Syndrome and Juvenile Myelo-Monocytic Leukemia, have been linked to gain-of-function mutations in the Shp2/PTPN11 gene, and this phosphatase also appears to be a cellular target of the Helicobacter pylori virulence factor CagA protein implicated in pathogenesis of gastric carcinoma. While Shp2 activity has been implicated in numerous signaling pathways, including the Ras/MAPK and JAK/STAT pathways, its physiological significance remains elusive to investigators. Furthermore, the requirement for Shp2 activity in development has been demonstrated in vertebrate as well as in invertebrate models. To examine the hypothesis that Shp2 acts primarily in one pathway in a specific cell/tissue type during a certain developmental stage, we generated Shp2 conditional mice to spatially/temporally dissect the functions of Shp2 tyrosine phosphatase. I report here that a loss-of-function mutation of Shp2 in embryonic central nervous system (CNS) leads to severe developmental impairment, including early postnatal lethality of the whole animal, impaired proliferation and differentiation of the neural stem cell, and defects in cell positioning of the cerebellum. These various defects are associated with disruption of growth factors and/or integrin-initiated Ras/MAPK signaling pathways. In the second mouse model, ablation of Shp2 in postnatal forebrain neurons causes an early-onset obesity, apparently due to defective leptin signaling. These Shp2 mutant mice recapitulate the obese phenotype of ob/ob and db/db mice, particularly the fatty liver and metabolic disorders due to leptin resistance. Importantly, this is the first mutant mouse model in which the development of obesity is separated from hyperphagia, and pharmaceutical augmentation of Shp2 activity in the brain may potentially be a novel and efficient therapeutic strategy for alleviation of leptin resistance in obese patients. In conclusion, this dissertation presents intensive studies on Shp2 activities in mammalian embryonic and adult CNS, suggesting that Shp2 plays distinct functions at different developmental stages.