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

Abstract

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). Both types of disease mutations are gain-of-function mutations because they induce SHP2 to constitutively adopt an open conformation, yet they have opposing effects on SHP2 catalytic activity. Here, we report that the catalytic activity of SHP2 is required for the pathogenic effects of Ptpn11 gain-of-function disease-associated mutations on the development of hydrocephalus in the mouse. Targeted pan-neuronal knock-in of the Ptpn11 activating mutation E76K resulted in hydrocephalus due to aberrant development of ependymal cells and their cilia. These pathogenic effects of the E76K mutation were completely suppressed by the additional mutation C459S, which abolishes catalytic activity of SHP2. Moreover, ependymal cells in NSML mice bearing the Ptpn11 inactivating mutation Y279C were also unaffected. Mechanistically, the Ptpn11E76K mutation induced developmental defects in ependymal cells by enhancing dephosphorylation and inhibition of the transcriptional 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 Ptpn11 gain-of-function disease mutations in the pathogenesis of hydrocephalus.

SHP2 mutations induce precocious gliogenesis of Noonan syndrome-derived iPSCs during neural development in vitro

“…3a, b). Ptpn11 E76K/+ /Nestin-Cre + conditional knock-in mice markedly increase the number of astrocytes in both cortex and hippocampus at 1 month old [63]. Ras-hyperactivating mutations, such as H-Ras G12V mutation and Nf1-inactivating mutation, cause an increase in gliogenesis in mice [64,65].…”

The impact of RASopathy-associated mutations on CNS development in mice and humans

“…Neural crest cell-specific Shp2 Q79R resulted in craniofacial defects and growth retardation [170]. Neural stem cellspecific expression of Shp2 E76K by using Nestin-Cre resulted in hydrocephalus due to aberrant development of ependymal cells [95]. In addition, Shp2 E76K -expressing mice showed hyperactivity accompanied by reduced anxiety behavior, and impaired motor function [95].…”

“…Neural stem cellspecific expression of Shp2 E76K by using Nestin-Cre resulted in hydrocephalus due to aberrant development of ependymal cells [95]. In addition, Shp2 E76K -expressing mice showed hyperactivity accompanied by reduced anxiety behavior, and impaired motor function [95]. Global Shp2 D61Y expression resulted in embryonic lethality, while epiblastspecific Shp2 D61Y expression induced embryonic cardiac defects [173].…”

Protein Phosphatases—A Touchy Enemy in the Battle Against Glioblastomas: A Review

“…Tyrosine-protein phosphatase non-receptor type 11 (PTPN11; also known as PTP-1D, PTP-2C, or SHP2) is a PTP activated mainly by RTKs and is one of the representative PTPs that have oncogenic roles in various cancers [24,33,80,81,82,83,84,85]. Dysregulation of SHP2 function because of germline mutations is involved in the pathogenesis of hereditary diseases, such as Noonan syndrome and Leopard syndrome, as well as in oncogenesis and malignancy of neoplasms [24,33,80,81,82,83,84,85,86,87]. The major signaling pathway regulated by SHP2 is the Ras-Raf-ERK (MAPK) cascade [33,80,81,82,83,84].…”

“…The major signaling pathway regulated by SHP2 is the Ras-Raf-ERK (MAPK) cascade [33,80,81,82,83,84]. Both the hereditary diseases and oncogenic signaling triggered by dysregulation of SHP2 are known to be mediated by alterations of MAPK cascade activity [33,81,82,85,86,87]. Although SHP2 is reported to negatively regulate proto-oncogenes, such as STAT3, by dephosphorylation [88,89], SHP2 as a positive regulator of the MAPK cascade is reported to contribute as a proto-oncogene.…”