Phosphatase-Dependent and -Independent Functions of Shp2 in Neural Crest Cells Underlie LEOPARD Syndrome Pathogenesis

Dana-Farber Cancer Institute, Department of Pediatric Oncology, Harvard Medical School, Boston, MA 02115, USA.
Developmental Cell (Impact Factor: 9.71). 05/2010; 18(5):750-62. DOI: 10.1016/j.devcel.2010.03.009
Source: PubMed


The tyrosine phosphatase SHP2 (PTPN11) regulates cellular proliferation, survival, migration, and differentiation during development. Germline mutations in PTPN11 cause Noonan and LEOPARD syndromes, which have overlapping clinical features. Paradoxically, Noonan syndrome mutations increase SHP2 phosphatase activity, while LEOPARD syndrome mutants are catalytically impaired, raising the possibility that SHP2 has phosphatase-independent roles. By comparing shp2-deficient zebrafish embryos with those injected with mRNA encoding LEOPARD syndrome point mutations, we identify a phosphatase- and Erk-dependent role for Shp2 in neural crest specification and migration. We also identify an unexpected phosphatase- and Erk-independent function, mediated through its SH2 domains, which is evolutionarily conserved and prevents p53-mediated apoptosis in the brain and neural crest. Our results indicate that previously enigmatic aspects of LEOPARD syndrome pathogenesis can be explained by the combined effects of loss of Shp2 catalytic function and retention of an SH2 domain-mediated role that is essential for neural crest cell survival.

Download full-text


Available from: Benjamin G Neel,
  • Source
    • "These abnormal developmental syndromes have several features in common, including heart defects, skin abnormalities, and distinctive facial features. How Erk overactivation leads to these phenotypes is not known; however, in a zebrafish model of LEOPARD syndrome , it has been suggested that downregulation of foxd3 and sox10 by Erk is important for normal neural crest migration, with subsequent effects on development (Stewart et al., 2010). Here, we suggest that Gata6 activation by Erk plays a central role in the zebrafish development related to neural crest migration . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Proper neural crest development and migration is critical during embryonic development, but the molecular mechanisms regulating this process remain incompletely understood. Here, we show that the protein kinase Erk, which plays a central role in a number of key developmental processes in vertebrates, is regulated in the developing neural crest by p21-activated protein kinase 1 (Pak1). Furthermore, we show that activated Erk signals by phosphorylating the transcription factor Gata6 on a conserved serine residue to promote neural crest migration and proper formation of craniofacial structures, pigment cells, and the outflow tract of the heart. Our data suggest an essential role for Pak1 as an Erk activator, and Gata6 as an Erk target, during neural crest development.
    Developmental Cell 05/2014; 29(3):350-9. DOI:10.1016/j.devcel.2014.04.003 · 9.71 Impact Factor
  • Source
    • "In zebrafish, Shp2 knockdown embryos show a reduction of the body axis extension at 10 hours post fertilization (hpf) that is consistent with gastrulation defects. In addition, at later stages, the embryos are shorter and develop a hammerhead phenotype [26], [27]. These data show that Shp2 is a crucial player in the development of many different organisms. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The PTPN11 (protein-tyrosine phosphatase, non-receptor type 11) gene encodes SHP2, a cytoplasmic PTP that is essential for vertebrate development. Mutations in PTPN11 are associated with Noonan and LEOPARD syndrome. Human patients with these autosomal dominant disorders display various symptoms, including short stature, craniofacial defects and heart abnormalities. We have used the zebrafish as a model to investigate the role of Shp2 in embryonic development. The zebrafish genome encodes two ptpn11 genes, ptpn11a and ptpn11b. Here, we report that ptpn11a is expressed constitutively and ptpn11b expression is strongly upregulated during development. In addition, the products of both ptpn11 genes, Shp2a and Shp2b, are functional. Target-selected inactivation of ptpn11a and ptpn11b revealed that double homozygous mutants are embryonic lethal at 5-6 days post fertilization (dpf). Ptpn11a-/-ptpn11b-/- embryos showed pleiotropic defects from 4 dpf onwards, including reduced body axis extension and craniofacial defects, which was accompanied by low levels of phosphorylated Erk at 5 dpf. Interestingly, defects in homozygous ptpn11a-/- mutants overlapped with defects in the double mutants albeit they were milder, whereas ptpn11b-/- single mutants did not show detectable developmental defects and were viable and fertile. Ptpn11a-/-ptpn11b-/- mutants were rescued by expression of exogenous ptpn11a and ptpn11b alike, indicating functional redundance of Shp2a and Shp2b. The ptpn11 mutants provide a good basis for further unravelling of the function of Shp2 in vertebrate development.
    PLoS ONE 04/2014; 9(4):e94884. DOI:10.1371/journal.pone.0094884 · 3.23 Impact Factor
  • Source
    • "Resounding evidence of a role for non-coding RNAs in neural crest cell development has been shown through the removal of DICER specifically in the neural crest cell lineage in mouse embryos (Huang et al., 2010). In addition, the role of kinases (Phillips et al., 2012), phosphatases (Roffers-Agarwal et al., 2012; Stewart et al., 2010) and sumoylation (Lee et al., 2012) have recently come to light. Yet, despite this focus, there has been little investigation to the role of ubiquitination. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neural crest cells are a transient population of stem cells that give rise to a diverse range of cell types during embryonic development. Through gain-of-function and loss-of-function studies in several model organisms many key signalling pathways and cell-type specific transcription factors essential for neural crest cell development have been identified. However, the role of post-translational regulation remains largely unexplored. Here we review this cell type with a foray into the known and potential roles of the ubiquitination system in key signalling events during neural crest cell development.
    The international journal of biochemistry & cell biology 02/2013; 45(6). DOI:10.1016/j.biocel.2013.02.014 · 4.05 Impact Factor
Show more