Syk kinase is phosphorylated in specific areas of the developing nervous system

Hatterer, Eric; Benon, Aurélien; Chounlamountri, Naura; Watrin, Chantal; Angibaud, Julie; Jouanneau, Emmanuel; Boudin, Hélène; Honnorat, Jérôme; Pellier‐Monnin, Véronique; Noraz, Nelly

doi:10.1016/j.neures.2011.02.008

Cited by 9 publications

(9 citation statements)

References 39 publications

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“…Consistent with a role for ITAM-based signaling in developmental events contributing to the establishment of neuronal connectivity, we showed in a previous study that Syk is phosphorylated on tyrosine residues representative of an active form of the kinase in regions of synaptogenesis and in specialized populations of migrating cells or projecting axons (Hatterer et al, 2011). Notably, since neurons are devoid of classical immunoreceptors, the neuronal function of ITAM-based signaling is likely to be linked to unrelated receptors that use it in a co-optive manner.…”

Section: Introductionsupporting

confidence: 87%

“…In hippocampal neurons, Syk phosphorylation was low at basal level and increased upon ephrin ligand binding; collapse was slow (45 min; Fig. S1) Hatterer et al, 2011). By contrast, in commissural neurons, Syk phosphorylation was constitutively elevated and decreased upon ephrin binding, although the difference did not reach statistical significance; collapse was rapid (5 min).…”

Section: Discussion Syk Activity and Growth Cone Responsiveness To Gumentioning

confidence: 92%

“…Tissue sections were obtained from E11-13 embryos as previously described (Hatterer et al, 2011). For immunostaining, sections were first incubated in blocking buffer PBS-T (0.3% Triton X-100) containing 3% BSA for 1 h at RT and then with primary antibodies overnight at 4°C.…”

Section: Immunofluorescent Labeling On Tissue Sectionsmentioning

confidence: 99%

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Syk kinases are required for spinal commissural axon repulsion at the midline via ephrin/Eph pathway

et al. 2016

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In the hematopoietic system, Syk family tyrosine kinases are essential components of immunoreceptor ITAM-based signaling. While there is increasing data indicating the involvement of immunoreceptors in neural functions, the contribution of Syk kinases remains obscure. Previously, we identified phosphorylated forms of Syk kinases in specialized populations of migrating neurons or projecting axons. Moreover, we identified ephrin/Eph as guidance molecules utilizing the ITAM-bearing CD3zeta (Cd247) and associated Syk kinases for the growth cone collapse response induced in vitro. Here, we show that in the developing spinal cord, Syk is phosphorylated in navigating commissural axons. By analyzing axon trajectories in open-book preparations of Sykmouse embryos, we show that Syk kinases are dispensable for attraction towards the midline but confer growth cone responsiveness to repulsive signals that expel commissural axons from the midline. Known to serve a repulsive function at the midline, ephrin B3/EphB2 are obvious candidates for driving the Syk-dependent repulsive response. Indeed, Syk kinases were found to be required for ephrin B3-induced growth cone collapse in cultured commissural neurons. In fragments of commissural neuron-enriched tissues, Syk is in a constitutively phosphorylated state and ephrin B3 decreased its level of phosphorylation. Direct pharmacological inhibition of Syk kinase activity was sufficient to induce growth cone collapse. In conclusion, Syk kinases act as a molecular switch of growth cone adhesive and repulsive responses.

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Section: Introductionsupporting

confidence: 87%

Section: Discussion Syk Activity and Growth Cone Responsiveness To Gumentioning

confidence: 92%

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Syk kinases are required for spinal commissural axon repulsion at the midline via ephrin/Eph pathway

et al. 2016

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“…60 In support of the possible interplay between LAT and the BP4-BP5 mapping loci, copy number variants of the BP4-BP5 interval was associated with LAT differential expression in human lymphoblastoid cell lines. 45 Our findings suggest that LAT, like CD247 and ZAP70, [41][42][43][44] plays a role in neurogenesis and that perturbation of this pathway may lead to neurodevelopmental phenotypes. They also provide an interesting example of the non-random organization of the genome 61 as gene dosage modification of (at least) one and five of the 9 and 28 genes mapping within the 220 kb BP2-BP3 and 600 kb BP4-BP5 intervals can influence the PTEN-antagonized (phosphatase and tensin homolog) PI3K/AKT and Ras/MAPK pathways: LAT, TAOK2, that encodes a PTEN-binding MAP kinase kinase kinase essential for dendrite morphogenesis, 62,63 MVP, the product of which interacts with PTEN and regulates its intracellular localization, 59,64,65 MAPK3, KCTD13, 37 and CDIPT (MIM: 605893) encoding an enzyme of the phosphatidylinositol synthesis pathway.…”

Section: Discussionmentioning

confidence: 70%

“…CD3z) and ZAP70. [41][42][43][44] Both genes encode proteins belonging to the T cells receptor's signaling module similar to LAT. We observed that the overexpression of the CD247 and ZAP70 in zebrafish embryos recapitulates the phenotype observed upon LAT overexpression, i.e., the decreased cell proliferation in the brain compared to control embryos ( Figure 3C).…”

Section: Lat Perturbation and Neuroanatomymentioning

confidence: 99%

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

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Arbogast

Jønch³

et al. 2017

The American Journal of Human Genetics

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Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. We assessed the drivers of the distal 16p11.2 duplication by overexpressing each of the nine encompassed genes in zebrafish. Only overexpression of LAT induced a reduction of brain proliferating cells and concomitant microcephaly. Consistently, suppression of the zebrafish ortholog induced an increase of proliferation and macrocephaly. These phenotypes were not unique to zebrafish; Lat knockout mice show brain volumetric changes. Consistent with the hypothesis that LAT dosage is relevant to the CNV pathology, we observed similar effects upon overexpression of CD247 and ZAP70, encoding members of the LAT signalosome. We also evaluated whether LAT was interacting with KCTD13, MVP, and MAPK3, major driver and modifiers of the proximal 16p11.2 600 kb BP4-BP5 syndromes, respectively. Co-injected embryos exhibited an increased microcephaly, suggesting the presence of genetic interaction. Correspondingly, carriers of 1.7 Mb BP1-BP5 rearrangements that encompass both the BP2-BP3 and BP4-BP5 loci showed more severe phenotypes. Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes.

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Distribution of spleen tyrosine kinase and tau phosphorylated at tyrosine 18 in a mouse model of tauopathy and in the human hippocampus

2017

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Syk kinase is phosphorylated in specific areas of the developing nervous system

Cited by 9 publications

References 39 publications

Syk kinases are required for spinal commissural axon repulsion at the midline via ephrin/Eph pathway

Syk kinases are required for spinal commissural axon repulsion at the midline via ephrin/Eph pathway

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Distribution of spleen tyrosine kinase and tau phosphorylated at tyrosine 18 in a mouse model of tauopathy and in the human hippocampus

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