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

Abstract

Background: Noonan syndrome (NS) is a developmental disorder caused by mutations of Src homology 2 domaincontaining protein tyrosine phosphatase 2 (SHP2). Although NS patients have diverse neurological manifestations, the mechanisms underlying the involvement of SHP2 mutations in neurological dysfunction remain elusive. Methods: Induced pluripotent stem cells generated from dermal fibroblasts of three NS-patients (NS-iPSCs) differentiated to the neural cells by using two different culture systems, 2D-and 3D-cultured systems in vitro. Results: Here we represent that SHP2 mutations cause aberrant neural development. The NS-iPSCs exhibited impaired development of EBs in which BMP and TGF-β signalings were activated. Defective early neuroectodermal development of NS-iPSCs recovered by inhibition of both signalings and further differentiated into NPCs. Intriguingly, neural cells developed from NS-NPCs exhibited abundancy of the glial cells, neurites of neuronal cells, and low electrophysiological property. Those aberrant phenotypes were also detected in NS-cerebral organoids. SHP2 inhibition in the NS-NPCs and NS-cerebral organoids ameliorated those anomalies such as biased glial differentiation and low neural activity. Conclusion: Our findings demonstrate that SHP2 mutations contribute to precocious gliogenesis in NS-iPSCs during neural development in vitro.

Klotho inhibits neuronal senescence in human brain organoids

“…5c, d). After neurogenesis has been initiated, cortical brain organoids are known to exhibit waves of gliogenesis 24 , and we similarly observed the specification of GFAP expressing cells in our organoids (Supplementary Fig. 6a).…”

The RASopathies: from pathogenetics to therapeutics

“…Moreover, induced pluripotent stem cells (iPSCs) derived from NS patients with PTPN11 N308D and PTPN11 D61N displayed impaired early neuroectodermal development due to enhanced gliogenesis and shortened neurites. This phenotype was rescued by treatment with the preclinical compound PHPS1, a cell-permeable phospho-tyrosine mimetic that inhibits PTPN11 phosphatase activity ( Ju et al, 2020 ). Knock-in mouse models of Ptpn11 N308D/+ and Ptpn11 D61G/+ ( ) display small body size, facial dysmorphia, splenomegaly, and deficits in spatial learning and memory ( Araki et al, 2009 , 2004 ).…”

Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment

“…Although iPSC lines are a valuable resource for neurodevelopmental disease research, so far most of the cell lines generated for the various genes associated with Noonan syndrome have only been studied in the context of the Noonan-associated cardiomyopathy (RAF1 [162,163], LZTR1 [164], MRAS [165]) and juvenile myelomonocytic leukemia (PTPN11 [166]). Only one study aimed at analyzing neurodevelopment using iPSCs from three patients diagnosed with Noonan syndrome (NS-iPSCs) harboring mutations in PTPN11 [166]. Interestingly, embryoid bodies (EBs) generated from NS-iPSCs are not able to differentiate into neuroectoderm, which is driven by an activation of BMP and TGF-beta signaling.…”

“…The generated NS-neural cell lines both show increased gliogenesis as well as shortened neurites accompanied by lower spontaneous firing rates, respectively. These phenotypes are rescued via inhibition of PTPN11 indicating a role in the establishment of electrophysiological properties in NS-neural cells via an imbalanced population of neurons and glial cells as well as reduced neurite outgrowth [166].…”