Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine of key importance for controlling embryogenesis and tissue homeostasis. How TGF-beta signals are attenuated and terminated is not well understood. Here, we show that TMEPAI, a direct target gene of TGF-beta signaling, antagonizes TGF-beta signaling by interfering with TGF-beta type I receptor (TbetaRI)-induced R-Smad phosphorylation. TMEPAI can directly interact with R-Smads via a Smad interaction motif. TMEPAI competes with Smad anchor for receptor activation for R-Smad binding, thereby sequestering R-Smads from TbetaRI kinase activation. In mammalian cells, ectopic expression of TMEPAI inhibited TGF-beta-dependent regulation of plasminogen activator inhibitor-1, JunB, cyclin-dependent kinase inhibitors, and c-myc expression, whereas specific knockdown of TMEPAI expression prolonged duration of TGF-beta-induced Smad2 and Smad3 phosphorylation and concomitantly potentiated cellular responsiveness to TGF-beta. Consistently, TMEPAI inhibits activin-mediated mesoderm formation in Xenopus embryos. Therefore, TMEPAI participates in a negative feedback loop to control the duration and intensity of TGF-beta/Smad signaling.

Extracellular stimuli in the injured CNS, such as chondroitin sulfate proteoglycans, inhibit axon growth through activation of the small GTPase RhoA. This RhoA activation increases intracellular Ca2+ that converges on an HDAC6-dependent pathway to deacetylate Miro1. Deacetylation of Miro1 decreases mitochondrial transport and attenuates axon growth.

In BriefDimethyl fumarate (DMF) is a reactive fumarate ester used in the treatment of relapsing remitting multiple sclerosis; however, the neuroprotective mechanisms of DMF action are incompletely understood. The results uncover novel DMF-modified cysteine residues in neurons and astrocytes, including cytoskeletal proteins whose modulation by DMF may alter the response to neurodegenerative cues and myelination. Graphical Abstract Highlights• Dimethyl fumarate covalently modifies cysteine residues in neurons and astrocytes.• Cofilin-1, tubulin and collapsin response mediator protein 2 (CRMP2) are targets.• DMF-modified cofilin-1 reduces actin-severing ability, preserving filamentous actin.

Inhibition of Cdh1-APC decreases protein synthesis in cortical neurons Cdh1 interacts with translational machinery including stress granule proteinsCdh1-APC regulates the formation of stress granules in neurons through FMRP Cdh1-APC has a dual role in protein homeostasis

Neurodevelopmental psychiatric disorders including schizophrenia (Sz) and attention deficit hyperactivity disorder (ADHD) are chronic mental illnesses, which place costly and painful burdens on patients, their families and society. In recent years, the epidermal growth factor (EGF) family member Neuregulin 1 (NRG1) and one of its receptors, ErbB4, have received considerable attention due to their regulation of inhibitory local neural circuit mechanisms important for information processing, attention, and cognitive flexibility. Here we examine an emerging body of work indicating that either decreasing NRG1–ErbB4 signaling in fast-spiking parvalbumin positive (PV+) interneurons or increasing it in vasoactive intestinal peptide positive (VIP+) interneurons could reactivate cortical plasticity, potentially making it a future target for gene therapy in adults with neurodevelopmental disorders. We propose preclinical studies to explore this model in prefrontal cortex (PFC), but also review the many challenges in pursuing cell type and brain-region-specific therapeutic approaches for the NRG1 system.

The ephrin-A1 and EphA receptors are frequently highly expressed in different human cancers, suggesting that they may promote tumor development and progression. We generated transgenic mice carrying Fabpl 4xat-132 ephrin-A1, which express ephrin-A1 in the intestinal epithelial cells. Those mice were then mated with Apc min/ þ mice to produce the compound mice, which overexpress ephrin-A1 in the intestinal tumors of Apc min/ þ mice. We compared the number, size and histopathological features of the intestinal tumors in the Fabpl 4xat-132 ephrin-A1/Apc min/ þ compound mice with those of the Apc min/ þ mice. The compound mice showed an increased number of intestinal tumors, significantly in the large intestine, and developed more invasive tumors. Among the 20 mice of each type examined, 5 Apc min/ þ mice developed 5 invasive tumors, 1 invasive tumor in each mouse, in the proximal or middle portions of the small intestine. On the other hand, 14 out of 20 compound mice developed 29 invasive tumors and 16 of them were in the distal small intestine and the large intestine, where transgenic ephrin-A1 was highly expressed. These results suggested that the increased expression of ephrin-A1 accelerated the malignant progression of the intestinal adenoma to invasive tumors.

Mutations in the human kinesin family member 5A (KIF5A) gene were recently identified as a genetic cause of amyotrophic lateral sclerosis (ALS). Several KIF5A ALS variants cause exon 27 skipping and are predicted to produce motor proteins with an altered C‐terminal tail (referred to as ΔExon27). However, the underlying pathogenic mechanism is still unknown. Here, we confirm the expression of KIF5A mutant proteins in patient iPSC‐derived motor neurons. We perform a comprehensive analysis of ΔExon27 at the single‐molecule, cellular, and organism levels. Our results show that ΔExon27 is prone to form cytoplasmic aggregates and is neurotoxic. The mutation relieves motor autoinhibition and increases motor self‐association, leading to drastically enhanced processivity on microtubules. Finally, ectopic expression of ΔExon27 in Drosophila melanogaster causes wing defects, motor impairment, paralysis, and premature death. Our results suggest gain‐of‐function as an underlying disease mechanism in KIF5A‐associated ALS.

Mutations in the human kinesin family member 5A (KIF5A) gene were recently identified as a genetic cause of amyotrophic lateral sclerosis (ALS). Several KIF5A ALS variants cause exon 27 skipping and produce motor proteins with an altered C-terminal tail (referred to as ΔExon27). However, the underlying pathogenic mechanism is still unknown. In this study, we performed a comprehensive analysis of ΔExon27 at the single-molecule, cellular, and organism levels. Our results show that ΔExon27 is prone to form cytoplasmic aggregates and is neurotoxic. The mutation relieves motor autoinhibition and increases motor self-association, leading to drastically enhanced processivity on microtubules. Finally, ectopic expression of ΔExon27 in Drosophila melanogaster causes wing defects, motor impairment, paralysis and premature death. Our results suggest gain of function as an underlying disease mechanism in KIF5A-associated ALS.