Pridopidine in early-stage manifest Huntington's disease: a phase 3 trial.

Huntington's disease (HD) is a rare, neurodegenerative disorder for which only symptomatic treatments are available. The PROOF-HD study was a randomized, double-blind, placebo-controlled phase 3 trial evaluating the efficacy and safety of pridopidine, a selective Sigma-1 receptor agonist, in HD. The primary and key secondary endpoints, change in total functional capacity (TFC) and composite Unified Huntington's Disease Rating Scale (cUHDRS) score at week 65, were not met in the overall population.

Microtubule-binding protein MAP1B regulates interstitial axon branching of cortical neurons via the tubulin tyrosination cycle.

Regulation of directed axon guidance and branching during development is essential for the generation of neuronal networks. However, the molecular mechanisms that underlie interstitial (or collateral) 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).

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

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 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.

Drebrin Regulates Collateral Axon Branching in Cortical Layer II/III Somatosensory Neurons.

Proper cortical lamination is essential for cognition, learning, and memory. Within the somatosensory cortex, pyramidal excitatory neurons elaborate axon collateral branches in a laminar-specific manner that dictates synaptic partners and overall circuit organization. Here, we leverage both male and female mouse models, single-cell labeling and imaging approaches to identify intrinsic regulators of laminar-specific collateral, also termed interstitial, axon branching.

Palmitoylation regulates neuropilin-2 localization and function in cortical neurons and conveys specificity to semaphorin signaling via palmitoyl acyltransferases.

Secreted semaphorin 3F (Sema3F) and semaphorin 3A (Sema3A) exhibit remarkably distinct effects on deep layer excitatory cortical pyramidal neurons; Sema3F mediates dendritic spine pruning, whereas Sema3A promotes the elaboration of basal dendrites. Sema3F and Sema3A signal through distinct holoreceptors that include neuropilin-2 (Nrp2)/plexinA3 (PlexA3) and neuropilin-1 (Nrp1)/PlexA4, respectively. We find that Nrp2 and Nrp1 are S-palmitoylated in cortical neurons and that palmitoylation of select Nrp2 cysteines is required for its proper subcellular localization, cell surface clustering, and also for Sema3F/Nrp2-dependent dendritic spine pruning in cortical neurons, both in vitro and in vivo.

Netrin-Mediated Axon Guidance to the CNS Midline Revisited.

Varadarajan et al. (2017)-in this issue of Neuron-and Dominici et al. (2017)-published online at Nature-independently show that floor plate-derived netrin-1 is dispensable for commissural neuron axon guidance to the CNS midline during development.

Axon Dynamics during Neocortical Laminar Innervation.

The cerebral cortex is a densely interconnected structure with neural circuits that form between cortical laminae and also between distinct cortical areas. However, the precise cell biological and developmental mechanisms that underlie the formation of these neural circuits remain unknown. Here, we visualize laminar innervation of the developing mouse cerebral cortex by layer II/III pyramidal neurons in real time, describing cytoskeletal dynamics during this process.

On and off retinal circuit assembly by divergent molecular mechanisms.

Direction-selective responses to motion can be to the onset (On) or cessation (Off) of illumination. Here, we show that the transmembrane protein semaphorin 6A and its receptor plexin A2 are critical for achieving radially symmetric arborization of On starburst amacrine cell (SAC) dendrites and normal SAC stratification in the mouse retina. Plexin A2 is expressed in both On and Off SACs; however, semaphorin 6A is expressed in On SACs.

Neurogenin2 regulates the initial axon guidance of cortical pyramidal neurons projecting medially to the corpus callosum.

Background: The formation of the mammalian central nervous system requires the establishment of complex neural circuits between a diverse array of neuronal subtypes. Here we report that the proneural transcription factor Neurogenin2 (Ngn2) is crucial for the proper specification of cortical axon projections.

Results: The genetic loss of Ngn2 in mice results in fewer callosal axons projecting towards the midline as well as abnormal midline crossing.

TGF-beta signaling specifies axons during brain development.

In the mammalian brain, the specification of a single axon and multiple dendrites occurs early in the differentiation of most neuron types. Numerous intracellular signaling events for axon specification have been described in detail. However, the identity of the extracellular factor(s) that initiate neuronal polarity in vivo is unknown.

Regulation of iron homeostasis mediated by the heme-binding protein Dap1 (damage resistance protein 1) via the P450 protein Erg11/Cyp51.

Fungal infections arise frequently in immunocompromised patients, and sterol synthesis is a primary pathway targeted by antifungal drugs. In particular, the P450 protein Erg11/Cyp51 catalyzes a critical step in ergosterol synthesis, and the azole class of antifungal drugs inhibits Erg11. Dap1 is a heme-binding protein related to cytochrome b5 that activates Erg11, so that cells lacking Dap1 accumulate the Erg11 substrate and are hypersensitive to Erg11 inhibitors.

Phosphorylation of Neurogenin2 specifies the migration properties and the dendritic morphology of pyramidal neurons in the neocortex.

The molecular mechanisms specifying the dendritic morphology of different neuronal subtypes are poorly understood. Here we demonstrate that the bHLH transcription factor Neurogenin2 (Ngn2) is both necessary and sufficient for specifying the dendritic morphology of pyramidal neurons in vivo by specifying the polarity of its leading process during the initiation of radial migration. The ability of Ngn2 to promote a polarized leading process outgrowth requires the phosphorylation of a single tyrosine residue at position 241, an event that is neither involved in Ngn2 direct transactivation properties nor its proneural function.

Hpr6.6 protein mediates cell death from oxidative damage in MCF-7 human breast cancer cells.

Reactive oxygen species (ROS) cause cell death and are associated with a variety of maladies, from trauma and infection to organ degeneration and cancer. Cells mount a complex response to oxidative damage that includes signaling from transmembrane receptors and intracellular kinases. We have analyzed the response to oxidative damage in human breast cancer cells expressing the Hpr6.

Overexpression of the receptor tyrosine kinase Tie-1 intracellular domain in breast cancer.

Objective: Tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Tie-1) is a receptor tyrosine kinase that regulates angiogenesis and antiapoptotic survival signaling. Tie-1 expression is generally associated with endothelial cells and neovascularization. We previously identified Tie-1 in human breast tumor samples using a PCR-based screen for protein kinases expressed in breast tumors.

Saccharomyces cerevisiae Dap1p, a novel DNA damage response protein related to the mammalian membrane-associated progesterone receptor.

The response to damage is crucial for cellular survival, and eukaryotic cells require a broad array of proteins for an intact damage response. We have found that the YPL170W (DAP1 [for damage response protein related to membrane-associated progesterone receptors]) gene is required for growth in the presence of the methylating agent methyl methanesulfonate (MMS). The DAP1 open reading frame shares homology with a broadly conserved family of membrane-associated progesterone receptors (MAPRs).