Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth.

Structural microtubule associated proteins (MAPs) stabilize microtubules, a property that was thought to be essential for development, maintenance and function of neuronal circuits. However, deletion of the structural MAPs in mice does not lead to major neurodevelopment defects. Here we demonstrate a role for MAP6 in brain wiring that is independent of microtubule binding. We find that MAP6 deletion disrupts brain connectivity and is associated with a lack of post-commissural fornix fibres. MAP6 contributes to fornix development by regulating axonal elongation induced by Semaphorin 3E. We show that MAP6 acts downstream of receptor activation through a mechanism that requires a proline-rich domain distinct from its microtubule-stabilizing domains. We also show that MAP6 directly binds to SH3 domain proteins known to be involved in neurite extension and semaphorin function. We conclude that MAP6 is critical to interface guidance molecules with intracellular signalling effectors during the development of cerebral axon tracts

Alpine ethnobotany in Italy: traditional knowledge of gastronomic and medicinal plants among the Occitans of the upper Varaita valley, Piedmont

A gastronomic and medical ethnobotanical study was conducted among the Occitan communities living in Blins/Bellino and Chianale, in the upper Val Varaita, in the Piedmontese Alps, North-Western Italy, and the traditional uses of 88 botanical taxa were recorded. Comparisons with and analysis of other ethnobotanical studies previously carried out in other Piemontese and surrounding areas, show that approximately one fourth of the botanical taxa quoted in this survey are also known in other surrounding Occitan valleys. It is also evident that traditional knowledge in the Varaita valley has been heavily eroded. This study also examined the local legal framework for the gathering of botanical taxa, and the potential utilization of the most quoted medicinal and food wild herbs in the local market, and suggests that the continuing widespread local collection from the wild of the aerial parts of Alpine wormwood for preparing liqueurs (Artemisia genipi, A. glacialis, and A. umbelliformis) should be seriously reconsidered in terms of sustainability, given the limited availability of these species, even though their collection is culturally salient in the entire study area

Modeling a disease-correlated tubulin mutation in budding yeast reveals insight into MAP-mediated dynein function

International audienceThe authors of this study employ budding yeast to model a disease-correlated tubulin mutation to determine how it leads to microtubule dysfunction. They find that the mutation leads to alterations in microtubule dynamics, tubulin isotype usage, and a spindle positioning defect that is due to disrupted microtubule-binding by a dynein regulator

Defective tubulin detyrosination causes structural brain abnormalities with cognitive deficiency in humans and mice

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Defective tubulin detyrosination causes structural brain abnormalities with cognitive deficiency in humans and mice

Reversible detyrosination of tubulin, the building block of microtubules, is crucial for neuronal physiology. Enzymes responsible for detyrosination were recently identified as complexes of vasohibins (VASHs) one or two with small VASH-binding protein (SVBP). Here we report three consanguineous families, each containing multiple individuals with biallelic inactivation of SVBP caused by truncating variants (p.Q28∗ and p.K13Nfs∗18). Affected individuals show brain abnormalities with microcephaly, intellectual disability and delayed gross motor and speech development. Immunoblot testing in cells with pathogenic SVBP variants demonstrated that the encoded proteins were unstable and non-functional, resulting in a complete loss of VASH detyrosination activity. Svbp knockout mice exhibit drastic accumulation of tyrosinated tubulin and a reduction of detyrosinated tubulin in brain tissue. Similar alterations in tubulin tyrosination levels were observed in cultured neurons and associated with defects in axonal differentiation and architecture. Morphological analysis of the Svbp knockout mouse brains by anatomical magnetic resonance imaging showed a broad impact of SVBP loss, with a 7% brain volume decrease, numerous structural defects and a 30% reduction of some white matter tracts. Svbp knockout mice display behavioural defects, including mild hyperactivity, lower anxiety and impaired social behaviour. They do not, however, show prominent memory defects. Thus, SVBP-deficient mice recapitulate several features observed in human patients. Altogether, our data demonstrate that deleterious variants in SVBP cause this neurodevelopmental pathology, by leading to a major change in brain tubulin tyrosination and alteration of microtubule dynamics and neuron physiolog

Schwann cell myelination requires Dynein function

<p>Abstract</p> <p>Background</p> <p>Interaction of Schwann cells with axons triggers signal transduction that drives expression of Pou3f1 and Egr2 transcription factors, which in turn promote myelination. Signal transduction appears to be mediated, at least in part, by cyclic adenosine monophosphate (cAMP) because elevation of cAMP levels can stimulate myelination in the absence of axon contact. The mechanisms by which the myelinating signal is conveyed remain unclear.</p> <p>Results</p> <p>By analyzing mutations that disrupt myelination in zebrafish, we learned that Dynein cytoplasmic 1 heavy chain 1 (Dync1h1), which functions as a motor for intracellular molecular trafficking, is required for peripheral myelination. In <it>dync1h1</it> mutants, Schwann cell progenitors migrated to peripheral nerves but then failed to express Pou3f1 and Egr2 or make myelin membrane. Genetic mosaic experiments revealed that robust Myelin Basic Protein expression required Dync1h1 function within both Schwann cells and axons. Finally, treatment of <it>dync1h1</it> mutants with a drug to elevate cAMP levels stimulated myelin gene expression.</p> <p>Conclusion</p> <p>Dync1h1 is required for retrograde transport in axons and mutations of Dync1h1 have been implicated in axon disease. Our data now provide evidence that Dync1h1 is also required for efficient myelination of peripheral axons by Schwann cells, perhaps by facilitating signal transduction necessary for myelination.</p