Dataset Information

MAP1B Regulates Cortical Neuron Interstitial Axon Branching Through the Tubulin Tyrosination Cycle.

ABSTRACT: Regulation of directed axon guidance and branching during development is essential for the generation of neuronal networks. However, the molecular mechanisms that underlie interstitial axon branching in the mammalian brain remain unresolved. Here, we investigate interstitial axon branching in vivo using an approach for precise labeling of layer 2/3 callosal projection neurons (CPNs), allowing for quantitative analysis of axonal morphology at high acuity and also manipulation of gene expression in well-defined temporal windows. We find that the GSK3β serine/threonine kinase promotes interstitial axon branching in layer 2/3 CPNs by releasing MAP1B-mediated inhibition of axon branching. Further, we find that the tubulin tyrosination cycle is a key downstream component of GSK3β/MAP1B signaling. We propose that MAP1B functions as a brake on axon branching that can be released by GSK3β activation, regulating the tubulin code and thereby playing an integral role in sculpting cortical neuron axon morphology.

SUBMITTER: Ziak J

PROVIDER: S-EPMC10592918 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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MAP1B Regulates Cortical Neuron Interstitial Axon Branching Through the Tubulin Tyrosination Cycle.

Ziak Jakub J Dorskind Joelle J Trigg Brian B Sudarsanam Sriram S Hand Randal R Kolodkin Alex L AL

bioRxiv : the preprint server for biology 20231002

Regulation of directed axon guidance and branching during development is essential for the generation of neuronal networks. However, the molecular mechanisms that underlie interstitial axon branching in the mammalian brain remain unresolved. Here, we investigate interstitial axon branching <i>in vivo</i> using an approach for precise labeling of layer 2/3 callosal projection neurons (CPNs), allowing for quantitative analysis of axonal morphology at high acuity and also manipulation of gene expre ...[more]

PMID: 37873083

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Project description:BackgroundHypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder caused by sarcomeric gene variants and associated with left ventricular hypertrophy and diastolic dysfunction. The role of the microtubule network has recently gained interest with the findings that microtubule detyrosination (dTyr-MT) is markedly elevated in heart failure. Acute reduction of dTyr-MT by inhibition of the detyrosinase (VASH [vasohibin]/SVBP [small VASH-binding protein] complex) or activation of the tyrosinase (TTL [tubulin tyrosine ligase]) markedly improved contractility and reduced stiffness in human failing cardiomyocytes and thus posed a new perspective for HCM treatment. In this study, we tested the impact of chronic tubulin tyrosination in an HCM mouse model (Mybpc3 knock-in), in human HCM cardiomyocytes, and in SVBP-deficient human engineered heart tissues (EHTs).MethodsAdeno-associated virus serotype 9-mediated TTL transfer was applied in neonatal wild-type rodents, in 3-week-old knock-in mice, and in HCM human induced pluripotent stem cell-derived cardiomyocytes.ResultsWe show (1) TTL for 6 weeks dose dependently reduced dTyr-MT and improved contractility without affecting cytosolic calcium transients in wild-type cardiomyocytes; (2) TTL for 12 weeks reduced the abundance of dTyr-MT in the myocardium, improved diastolic filling, compliance, cardiac output, and stroke volume in knock-in mice; (3) TTL for 10 days normalized cell area in HCM human induced pluripotent stem cell-derived cardiomyocytes; (4) TTL overexpression activated transcription of tubulins and other cytoskeleton components but did not significantly impact the proteome in knock-in mice; (5) SVBP-deficient EHTs exhibited reduced dTyr-MT levels, higher force, and faster relaxation than TTL-deficient and wild-type EHTs. RNA sequencing and mass spectrometry analysis revealed distinct enrichment of cardiomyocyte components and pathways in SVBP-deficient versus TTL-deficient EHTs.ConclusionsThis study provides the first proof of concept that chronic activation of tubulin tyrosination in HCM mice and in human EHTs improves heart function and holds promise for targeting the nonsarcomeric cytoskeleton in heart disease.

Dataset Information

MAP1B Regulates Cortical Neuron Interstitial Axon Branching Through the Tubulin Tyrosination Cycle.

Publications

MAP1B Regulates Cortical Neuron Interstitial Axon Branching Through the Tubulin Tyrosination Cycle.

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