The Protein Tyrosine Phosphatase Shp2 Is Required for the Generation of Oligodendrocyte Progenitor Cells and Myelination in the Mouse Telencephalon

Abstract

The protein tyrosine phosphatase Shp2 (PTPN11) is crucial for normal brain development and has been implicated in dorsal telencephalic neuronal and astroglia cell fate decisions. However, its roles in the ventral telencephalon and during oligodendrogenesis in the telencephalon remain largely unknown. Shp2 gain-of-function (GOF) mutations are observed in Noonan syndrome, a type of RASopathy associated with multiple phenotypes, including cardiovascular, craniofacial, and neurocognitive abnormalities. To gain insight into requirements for Shp2 (LOF) and the impact of abnormal Shp2 GOF mutations, we used a Shp2 conditional mutant allele (LOF) and a cre inducible Shp2-Q79R GOF transgenic mouse in combination with Olig2 cre/ϩ mice to target embryonic ventral telencephalic progenitors and the oligodendrocyte lineage. In the absence of Shp2 (LOF), neuronal cell types originating from progenitors in the ventral telencephalon were generated, but oligodendrocyte progenitor cell (OPC) generation was severely impaired. Late embryonic and postnatal Shp2 cKOs showed defects in the generation of OPCs throughout the telencephalon and subsequent reductions in white matter myelination. Conversely, transgenic expression of the Shp2 GOF Noonan syndrome mutation resulted in elevated OPC numbers in the embryo and postnatal brain. Interestingly, expression of this mutation negatively influenced myelination as mice displayed abnormal myelination and fewer myelinated axons in the white matter despite elevated OPC numbers. Increased proliferating OPCs and elevated MAPK activity were also observed during oligodendrogenesis after expression of Shp2 GOF mutation. These results support the notion that appropriate Shp2 activity levels control the number as well as the differentiation of oligodendrocytes during development.

Selective neuronal expression of the SoxE factor, Sox8, in direct pathway striatal projection neurons of the developing mouse brain

“…In western blot, it recognizes a single 170 kDa band on NIH/3T3 whole cell lysates (manufacturer's datasheet). This antibody has previously been used to identify OPCs in the mouse telencephalon (see e.g., Ehrman et al, ).…”

“…This antibody has previously been used to identify OPCs in the mouse telencephalon (see e.g., Ehrman et al, 2014).…”

Molecular Diversity and Associated Phenotypic Spectrum of GermlineCBLMutations

“…Of note, conditional ablation of Braf in mouse neuroglial precursor cells was shown to result in defective myelination and oligodendrocyte differentiation [Galabova‐Kovacs et al., ]. Similarly, loss of Shp2 in the oligodendrocyte lineage, as well as transgenic expression of a NS‐associated Shp2 gain‐of‐function allele, results in severe abnormal myelination phenotypes [Ehrman et al., ]. Hence, the myelination defect observed in some individuals with a CBL mutation adds support to the impact of dysregulated RAS signaling on glial cell development.…”

Cell type-specific roles of RAS-MAPK signaling in learning and memory: Implications in neurodevelopmental disorders

“…For example, Gauthier and colleagues showed that knocking down SHP2 blocked neurogenesis and enhanced astrogenesis, suggesting that SHP2 plays a pivotal role in determining neuronal cell fate (Gauthier et al, 2007). A recent study showed that SHP2 also regulates the generation of oligodendrocyte progenitor cells in the mouse ventral telencephalon (Ehrman, Nardini, Ehrman, Rizvi, Gulick, Krenz et al, 2014). Importantly, gain-of-function mutations of PTPN11 are highly associated with the NS, which is a common autosomal dominant genetic disorder characterized by congenital heart defects, facial abnormalities, delayed growth, and cognitive impairment (Romano, Allanson, Dahlgren, Gelb, Hall, Pierpont et al, 2010).…”