Molecular genetic analysis of the protein tyrosine phosphatase Shp2 (PTPN11) in the mouse telencephalon

Lisa Ehrman1, Diana Nardini1, Tilat Rizvi1, Nancy Ratner1, Masato Nakafuku2, Jeffrey Robbins3, and Ronald R. Waclaw1
1Division of Experimental Hematology and Cancer Biology, 2Division of Developmental Biology, 3Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center Cincinnati, OH

Shp2 (PTPN11) is an intracellular protein tyrosine phosphatase that is critical for mediating cell signaling in response to growth factors.  Germline mutations in PTPN11 have been identified Noonan and LEOPARD syndrome patients.  Patients with either syndrome exhibit several congenital malformations including a variety of cardiovascular and skeletal defects.  In addition to these defects, there is also an increased incidence of learning disabilities and cognitive impairment observed in both syndromes. The specific brain abnormalities that lead to these neurocognitive defects remain unknown. The goal of our study is to utilize mouse genetics to understand the role of Shp2 (PTPN11) in the telencephalon, which is the region of the brain most associated with higher neural functions like cognition and emotion. To do this, we have generated a conditional deletion of Shp2 and a conditional misexpression of the Q79R Noonan Syndrome mutation in transgenic mice restricted to the ventral telencephalon and oligodendrocyte lineage with Olig2cre/+ mice.  Our results suggest that Shp2 is crucial for progenitor cell development in the embryonic telencephalon and in the generation of myelinating oligodendrocytes in telencephalic structures of the brain.  Current experiments are focused on identifying regional roles for Shp2 (PTPN11) in the development of cell types originating from the telencephalon and determining the cellular origins of the neurocognitive defects observed in these patients.