Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner

The catalytic activity of the phosphatase SHP2 is required for the proper development of ependymal cells in the mouse. SHP2 in brain development The phosphatase SHP2, which is encoded by Ptpn11, is autoinhibited under basal conditions and adopts an open conformation and becomes catalytically active when it binds to signaling partners. Although Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are both associated with gain-of-function mutations that promote the ability of SHP2 to adopt an open conformation, NS-associated mutations activate SHP2, whereas NSML-associated mutations are catalytically inactivating. Zheng et al. found that disease-associated mutations in Ptpn11 caused hydrocephalus in mice by interfering with the normal development of the cells that play an essential role in the transport of cerebrospinal fluid only if the mutation impaired the catalytic activity of SHP2. These findings suggest that both catalytic-dependent and catalytic-independent functions of SHP2 mediate these pathologies and that these differential requirements for catalytic activity in distinct processes may underlie the phenotypic differences between NS and NSML. Catalytically activating mutations in Ptpn11, which encodes the protein tyrosine phosphatase SHP2, cause 50% of Noonan syndrome (NS) cases, whereas inactivating mutations in Ptpn11 are responsible for nearly all cases of the similar, but distinct, developmental disorder Noonan syndrome with multiple lentigines (NSML; formerly called LEOPARD syndrome). However, both types of disease mutations are gain-of-function mutations because they cause SHP2 to constitutively adopt an open conformation. We found that the catalytic activity of SHP2 was required for the pathogenic effects of gain-of-function, disease-associated mutations on the development of hydrocephalus in the mouse. Targeted pan-neuronal knockin of a Ptpn11 allele encoding the active SHP2 E76K mutant resulted in hydrocephalus due to aberrant development of ependymal cells and their cilia. These pathogenic effects of the E76K mutation were suppressed by the additional mutation C459S, which abolished the catalytic activity of SHP2. Moreover, ependymal cells in NSML mice bearing the inactive SHP2 mutant Y279C were also unaffected. Mechanistically, the SHP2 E76K mutant induced developmental defects in ependymal cells by enhancing dephosphorylation and inhibition of the transcription activator STAT3. Whereas STAT3 activity was reduced in Ptpn11E76K/+ cells, the activities of the kinases ERK and AKT were enhanced, and neural cell–specific Stat3 knockout mice also manifested developmental defects in ependymal cells and cilia. These genetic and biochemical data demonstrate a catalytic-dependent role of SHP2 gain-of-function disease mutants in the pathogenesis of hydrocephalus.