Merlin isoform 2 in neurofibromatosis type 2–associated polyneuropathy

Schulz, Alexander; Baader, Stephan L.; Niwa‐Kawakita, Michiko; Jung, Marie Juliane; Bauer, Reinhard; Garcia, Claudia M.; Zoch, Ansgar; Schacke, Stephan; Hagel, Christian; Mautner, Victor‐Felix; Hanemann, C. Oliver; Dun, Xin‐Peng; Parkinson, David B.; Weis, Joachim; Schröder, Johann Michael; Gutmann, David H.; Giovannini, Marco; Morrison, Helen

doi:10.1038/nn.3348

Cited by 53 publications

(61 citation statements)

References 33 publications

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“…It regulates diverse cellular processes, such as the establishment of cell polarity, formation of cell-cell junctions and proliferation. Nf2 plays numerous roles in the nervous system, including promoting cell-cell adhesion during neural tube closure (McLaughlin et al, 2007), inhibiting glial cell proliferation (Giovannini et al, 2000;Houshmandi et al, 2009) and maintaining axonal integrity (Schulz et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

The tumor suppressor Nf2 regulates corpus callosum development by inhibiting the transcriptional coactivator Yap

Lavado¹,

Ware²,

Paré³

et al. 2014

Journal of Cell Science

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The corpus callosum connects cerebral hemispheres and is the largest axon tract in the mammalian brain. Callosal malformations are among the most common congenital brain anomalies and are associated with a wide range of neuropsychological deficits. Crossing of the midline by callosal axons relies on a proper midline environment that harbors guidepost cells emitting guidance cues to instruct callosal axon navigation. Little is known about what controls the formation of the midline environment. We find that two components of the Hippo pathway, the tumor suppressor Nf2 (Merlin) and the transcriptional coactivator Yap (Yap1), regulate guidepost development and expression of the guidance cue Slit2 in mouse. During normal brain development, Nf2 suppresses Yap activity in neural progenitor cells to promote guidepost cell differentiation and prevent ectopic Slit2 expression. Loss of Nf2 causes malformation of midline guideposts and Slit2 upregulation, resulting in callosal agenesis. Slit2 heterozygosity and Yap deletion both restore callosal formation in Nf2 mutants. Furthermore, selectively elevating Yap activity in midline neural progenitors is sufficient to disrupt guidepost formation, upregulate Slit2 and prevent midline crossing. The Hippo pathway is known for its role in controlling organ growth and tumorigenesis. Our study identifies a novel role of this pathway in axon guidance. Moreover, by linking axon pathfinding and neural progenitor behaviors, our results provide an example of the intricate coordination between growth and wiring during brain development.

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Section: Introductionmentioning

confidence: 99%

The tumor suppressor Nf2 regulates corpus callosum development by inhibiting the transcriptional coactivator Yap

Lavado¹,

Ware²,

Paré³

et al. 2014

Journal of Cell Science

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“…Work by Collard et al (1995) provided some of the first evidence for NF-H accumulations being a factor in the degenerative process of amyotrophic lateral sclerosis (ALS). More recent work by Schulz et al (2013) have shown that reduced phosphorylation of NF-H may be a contributing factor in neurofibromatosis type 2, and Sellner et al (2014) that NF-H may be a useful pathological and prognostic marker for acute encephalitis.…”

Section: Discussionmentioning

confidence: 99%

Monoclonal antibody Py recognizes neurofilament heavy chain and is a selective marker for large diameter neurons in the brain

et al. 2016

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Telephone: +44(0)1782 733875Acknowledgments: We would like to thank Prof. Glenn E Morris for his invaluable insights into the growth of the Py clones, and the production of antibodies for immunofluorescence.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. AbstractAlmost 30 years ago, the monoclonal antibody Py was developed to detect pyramidal neurons in the CA3 region of the rat hippocampus. The utility of this antibody quickly expanded when several groups discovered that it could be used to identify very specific populations of neurons in the normal, developing, and diseased or injured central nervous system. Despite this body of literature, the identity of the antigen that the Py antibody recognizes remained elusive. Here, immunoprecipitation experiments from the adult rat cortex identified the Py antigen as neurofilament heavy chain (NF-H). Double immunolabelling of sections through the rat brain using Py and NF-H antibodies confirmed the identity of the Py antigen, and reveal that Py/NF-H+ neurons appear to share the feature of being particularly large in diameter. These include the neurons of the gigantocellular reticular formation, pyramidal neurons of layers II/III and V of the cortex, cerebellar Purkinje neurons as well as CA3 pyramidal neurons. Taken together, this finding gives clarity to past work using the monoclonal Py antibody, and immediately expands our understanding of the importance of NF-H in neural development, functioning, and disease.

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“…An additional mechanism is suggested by recent results: Two alternatively spliced merlin isoforms were found to be expressed in the mammalian nervous system, only one of which, isoform 2, was found in axons [12]. Functional studies revealed that an isoform 2-dependent complex promotes activation of the GTPase RhoA, leading to neurofilament heavy chain phosphorylation [12].…”

Section: Histopathology and Pathogenesismentioning

confidence: 99%