Proper Frequency of Perinatal Retinal Waves Is Essential for the Precise Wiring of Visual Axons in Nonimage-Forming Nuclei.

The development of the visual system is a complex and multistep process characterized by the precise wiring of retinal ganglion cell (RGC) axon terminals with their corresponding neurons in the visual nuclei of the brain. Upon reaching primary image-forming nuclei (IFN), such as the superior colliculus and the lateral geniculate nucleus, RGC axons undergo extensive arborization that refines over the first few postnatal weeks. The molecular mechanisms driving this activity-dependent remodeling process, which is influenced by waves of spontaneous activity in the developing retina, are still not well understood.

A Zic2-regulated switch in a noncanonical Wnt/βcatenin pathway is essential for the formation of bilateral circuits.

The Wnt pathway is involved in a wide array of biological processes during development and is deregulated in many pathological scenarios. In neurons, Wnt proteins promote both axon extension and repulsion, but the molecular mechanisms underlying these opposing axonal responses are unknown. Here, we show that Wnt5a is expressed at the optic chiasm midline and promotes the crossing of retinal axons by triggering an alternative Wnt pathway that depends on the accumulation of βcatenin but does not activate the canonical pathway.

Expression of the cold thermoreceptor TRPM8 in rodent brain thermoregulatory circuits.

The cold- and menthol-activated ion channel transient receptor potential channel subfamily M member 8 (TRPM8) is the principal detector of environmental cold in mammalian sensory nerve endings. Although it is mainly expressed in a subpopulation of peripheral sensory neurons, it has also been identified in non-neuronal tissues. Here, we show, by in situ hybridization (ISH) and by the analysis of transgenic reporter expression in two different reporter mouse strains, that TRPM8 is also expressed in the central nervous system.

Morphological and functional changes in TRPM8-expressing corneal cold thermoreceptor neurons during aging and their impact on tearing in mice.

Morphological and functional alterations of peripheral somatosensory neurons during the aging process lead to a decline of somatosensory perception. Here, we analyze the changes occurring with aging in trigeminal ganglion (TG), TRPM8-expressing cold thermoreceptor neurons innervating the mouse cornea, which participate in the regulation of basal tearing and blinking and have been implicated in the pathogenesis of dry eye disease (DED). TG cell bodies and axonal branches were examined in a mouse line (TRPM8 -EYFP) expressing a fluorescent reporter.

Guidance of retinal axons in mammals.

In order to navigate through the surrounding environment many mammals, including humans, primarily rely on vision. The eye, composed of the choroid, sclera, retinal pigmented epithelium, cornea, lens, iris and retina, is the structure that receives the light and converts it into electrical impulses. The retina contains six major types of neurons involving in receiving and modifying visual information and passing it onto higher visual processing centres in the brain.

Fine-tuned SRF activity controls asymmetrical neuronal outgrowth: implications for cortical migration, neural tissue lamination and circuit assembly.

The stimulus-regulated transcription factor Serum Response Factor (SRF) plays an important role in diverse neurodevelopmental processes related to structural plasticity and motile functions, although its precise mechanism of action has not yet been established. To further define the role of SRF in neural development and distinguish between cell-autonomous and non cell-autonomous effects, we bidirectionally manipulated SRF activity through gene transduction assays that allow the visualization of individual neurons and their comparison with neighboring control cells. In vitro assays showed that SRF promotes survival and filopodia formation and is required for normal asymmetric neurite outgrowth, indicating that its activation favors dendrite enlargement versus branching.

Ion channel profile of TRPM8 cold receptors reveals a role of TASK-3 potassium channels in thermosensation.

Animals sense cold ambient temperatures through the activation of peripheral thermoreceptors that express TRPM8, a cold- and menthol-activated ion channel. These receptors can discriminate a very wide range of temperatures from innocuous to noxious. The molecular mechanism responsible for the variable sensitivity of individual cold receptors to temperature is unclear.

Zic2-dependent axon midline avoidance controls the formation of major ipsilateral tracts in the CNS.

In bilaterally symmetric organisms, interhemispheric communication is essential for sensory processing and motor coordination. The mechanisms that govern axon midline crossing during development have been well studied, particularly at the spinal cord. However, the molecular program that determines axonal ipsilaterality remains poorly understood.

Epigenetic induction of the Ink4a/Arf locus prevents Schwann cell overproliferation during nerve regeneration and after tumorigenic challenge.

The number of Schwann cells is fitted to axonal length in peripheral nerves. This relationship is lost when tumorigenic stimuli induce uncontrolled Schwann cell proliferation, generating tumours such us neurofibromas and schwannomas. Schwann cells also re-enter the cell cycle following nerve injury during the process of Wallerian degeneration.

N-glycosylation of TRPM8 ion channels modulates temperature sensitivity of cold thermoreceptor neurons.

TRPM8 is a member of the transient receptor potential ion channel superfamily, which is expressed in sensory neurons and is activated by cold and cooling compounds, such as menthol. Activation of TRPM8 by agonists takes place through shifts in its voltage activation curve, allowing channel opening at physiological membrane potentials. Here, we studied the role of the N-glycosylation occurring at the pore loop of TRPM8 on the function of the channel.

Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea.

Basal tearing is crucial to maintaining ocular surface wetness. Corneal cold thermoreceptors sense small oscillations in ambient temperature and change their discharge accordingly. Deletion of the cold-transducing ion channel Transient receptor potential cation channel subfamily M member 8 (TRPM8) in mice abrogates cold responsiveness and reduces basal tearing without affecting nociceptor-mediated irritative tearing.

Pharmacological and functional properties of TRPM8 channels in prostate tumor cells.

Prostate cancer (PC) is a major health problem in adult males. TRPM8, a cationic TRP channel activated by cooling and menthol is upregulated in PC. However, the precise role of TRPM8 in PC is still unclear.

The emerging pharmacology of TRPM8 channels: hidden therapeutic potential underneath a cold surface.

Transient receptor potential melastatin 8 (TRPM8) is a non-selective cation channel activated by cold temperature and cooling agents. TRPM8 is expressed in a subpopulation of cold-sensitive sensory neurons, as well as in the male urogenital system. TRPM8 is markedly upregulated in prostate cancer and in other tumors such as breast adenocarcinoma and melanoma.

Lipid raft segregation modulates TRPM8 channel activity.

Transient receptor potential channels are a family of cation channels involved in diverse cellular functions. Most of these channels are expressed in the nervous system and play a key role in sensory physiology. TRPM8 (transient receptor potential melastatine 8), a member of this family, is activated by cold, cooling substances such menthol and icilin and voltage.

Transcriptional control of cholesterol biosynthesis in Schwann cells by axonal neuregulin 1.

A characteristic feature of many vertebrate axons is their wrapping by a lamellar stack of glially derived membranes known as the myelin sheath. Myelin is a cholesterol-rich membrane that allows for rapid saltatory nerve impulse conduction. Axonal neuregulins instruct glial cells on when and how much myelin they should produce.

A role for transcriptional repressor methyl-CpG-binding protein 2 and plasticity-related gene serum- and glucocorticoid-inducible kinase 1 in the induction of inflammatory pain states.

Activity-dependent changes in neurons of the rat superficial dorsal horn are crucial for the induction and maintenance of neuropathic and inflammatory pain states. To identify the molecular mechanisms underlying this sensitization of superficial dorsal horn neurons, we undertook a genome-wide microarray profiling of dorsal horn gene transcripts at various times after induction of peripheral inflammation of the rat ankle joint. At early time points, upregulation of gene expression dominated, but by 7 d, downregulation was predominant.

Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain.

Conditional mouse knock-outs provide an informative approach to drug target validation where no pharmacological blockers exist or global knock-outs are lethal. Here, we used the Cre-loxP system to delete BDNF in most nociceptive sensory neurons. Conditional null animals were healthy with no sensory neuron loss.

Functional aspects and mechanisms of TRPV1 involvement in neurogenic inflammation that leads to thermal hyperalgesia.

Neurogenic inflammation is produced by overstimulation of peripheral nociceptor terminals by injury or inflammation of tissues. Excessive activity of sensory neurons produces vasodilation, plasma extravasation and hypersensitivity. Mechanistically, neurogenic inflammation is due to the release of substances from primary sensory nerve terminals that act directly or indirectly at the peripheral terminals, either activating or sensitizing nociceptors, endothelial cells and immunocytes.

Identification of a tetramerization domain in the C terminus of the vanilloid receptor.

TRPV1 (transient receptor potential vanilloid receptor subtype 1) is a member of the TRP channel family gated by vanilloids, protons, and heat. Structurally, TRPV1 appears to be a tetramer formed by the assembly of four identical subunits around a central aqueous pore. The molecular determinants that govern its subunit oligomerization remain elusive.

Molecular architecture of the vanilloid receptor. Insights for drug design.

The transient receptor potential channel vanilloid receptor subunit 1 (TRPV1) is a molecular integrator of physical and chemical stimuli in the peripheral nociceptor terminals. TRPV1 is an ionotropic channel that plays a critical role in both thermal nociception and inflammatory hyperalgesia. Structure-function relationships are providing fundamental insights of the modular architecture of this neuronal receptor.

Regulated exocytosis contributes to protein kinase C potentiation of vanilloid receptor activity.

The vanilloid receptor-1 (TRPV1) plays a key role in the perception of peripheral thermal and inflammatory pain. TRPV1 expression and channel activity are notably up-regulated by proalgesic agents. The transduction pathways involved in TRPV1 sensitization are still elusive.