A Hairy End to a Chilling Event.

In the skin, sympathetic nerves, arrector pili muscles, and hair follicles form a tri-lineage unit to cause piloerection or goosebumps. In this issue of Cell, Schwartz et al. report that, beyond goosebumps, muscle-anchored nerves form "synapse-like" connections with hair follicle stem cells to promote hair regeneration in response to cold.

The sympathetic nervous system in development and disease.

The sympathetic nervous system prepares the body for 'fight or flight' responses and maintains homeostasis during daily activities such as exercise, eating a meal or regulation of body temperature. Sympathetic regulation of bodily functions requires the establishment and refinement of anatomically and functionally precise connections between postganglionic sympathetic neurons and peripheral organs distributed widely throughout the body. Mechanistic studies of key events in the formation of postganglionic sympathetic neurons during embryonic and early postnatal life, including axon growth, target innervation, neuron survival, and dendrite growth and synapse formation, have advanced the understanding of how neuronal development is shaped by interactions with peripheral tissues and organs. Recent progress has also been made in identifying how the cellular and molecular diversity of sympathetic neurons is established to meet the functional demands of peripheral organs. In this Review, we summarize current knowledge of signalling pathways underlying the development of the sympathetic nervous system. These findings have implications for unravelling the contribution of sympathetic dysfunction stemming, in part, from developmental perturbations to the pathophysiology of peripheral neuropathies and cardiovascular and metabolic disorders.

Transcytosis-mediated anterograde transport of TrkA receptors is necessary for sympathetic neuron development and function.

In neurons, many membrane proteins, synthesized in cell bodies, must be efficiently delivered to axons to influence neuronal connectivity, synaptic communication, and repair. Previously, we found that axonal targeting of TrkA neurotrophin receptors in sympathetic neurons occurs via an atypical transport mechanism called transcytosis, which relies on TrkA interactions with PTP1B, a protein tyrosine phosphatase. Here, we generated TrkAR685A mice, where TrkA receptor signaling is preserved, but its PTP1B-dependent transcytosis is disrupted to show that this mode of axonal transport is essential for sympathetic neuron development and autonomic function. TrkAR685A mice have decreased axonal TrkA levels in vivo, loss of sympathetic neurons, and reduced innervation of targets. The neuron loss and diminished target innervation phenotypes are specifically restricted to the developmental period when sympathetic neurons are known to rely on the TrkA ligand, nerve growth factor, for trophic support. Postnatal TrkAR685A mice exhibit reduced pupil size and eyelid ptosis, indicative of sympathetic dysfunction. Furthermore, we also observed a significant loss of TrkA-expressing nociceptive neurons in the dorsal root ganglia during development in TrkAR685A mice, suggesting that transcytosis might be a general mechanism for axonal targeting of TrkA receptors. Together, these findings establish the necessity of transcytosis in supplying TrkA receptors to axons, specifically during development, and highlight the physiological relevance of this axon targeting mechanism in the nervous system.

Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice.

Stability of neuronal connectivity is critical for brain functions, and morphological perturbations are associated with neurodegenerative disorders. However, how neuronal morphology is maintained in the adult brain remains poorly understood. Here, we identify Wnt5a, a member of the Wnt family of secreted morphogens, as an essential factor in maintaining dendritic architecture in the adult hippocampus and for related cognitive functions in mice. Wnt5a expression in hippocampal neurons begins postnatally, and its deletion attenuated CaMKII and Rac1 activity, reduced GluN1 glutamate receptor expression, and impaired synaptic plasticity and spatial learning and memory in 3-mo-old mice. With increased age, Wnt5a loss caused progressive attrition of dendrite arbors and spines in Cornu Ammonis (CA)1 pyramidal neurons and exacerbated behavioral defects. Wnt5a functions cell-autonomously to maintain CA1 dendrites, and exogenous Wnt5a expression corrected structural anomalies even at late-adult stages. These findings reveal a maintenance factor in the adult brain, and highlight a trophic pathway that can be targeted to ameliorate dendrite loss in pathological conditions.

Mechanisms of neurotrophin trafficking via Trk receptors.

In neurons, long-distance communication between axon terminals and cell bodies is a critical determinant in establishing and maintaining neural circuits. Neurotrophins are soluble factors secreted by post-synaptic target tissues that retrogradely control axon and dendrite growth, survival, and synaptogenesis of innervating neurons. Neurotrophins bind Trk receptor tyrosine kinases in axon terminals to promote endocytosis of ligand-bound phosphorylated receptors into signaling endosomes. Trk-harboring endosomes function locally in axons to acutely promote growth events, and can also be retrogradely transported long-distances to remote cell bodies and dendrites to stimulate cytoplasmic and transcriptional signaling necessary for neuron survival, morphogenesis, and maturation. Neuronal responsiveness to target-derived neurotrophins also requires the precise axonal targeting of newly synthesized Trk receptors. Recent studies suggest that anterograde delivery of Trk receptors is regulated by retrograde neurotrophin signaling. In this review, we summarize current knowledge on the functions and mechanisms of retrograde trafficking of Trk signaling endosomes, and highlight recent discoveries on the forward trafficking of nascent receptors.

Wnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis.

Wnts make up a large family of extracellular signaling molecules that play crucial roles in development and disease. A subset of noncanonical Wnts signal independently of the transcription factor ß-catenin by a mechanism that regulates key morphogenetic movements during embryogenesis. The best characterized noncanonical Wnt, Wnt5a, has been suggested to signal via a variety of different receptors, including the Ror family of receptor tyrosine kinases, the Ryk receptor tyrosine kinase, and the Frizzled seven-transmembrane receptors. Whether one or several of these receptors mediates the effects of Wnt5a in vivo is not known. Through loss-of-function experiments in mice, we provide conclusive evidence that Ror receptors mediate Wnt5a-dependent processes in vivo and identify Dishevelled phosphorylation as a physiological target of Wnt5a-Ror signaling. The absence of Ror signaling leads to defects that mirror phenotypes observed in Wnt5a null mutant mice, including decreased branching of sympathetic neuron axons and major defects in aspects of embryonic development that are dependent upon morphogenetic movements, such as severe truncation of the caudal axis, the limbs, and facial structures. These findings suggest that Wnt5a-Ror-Dishevelled signaling constitutes a core noncanonical Wnt pathway that is conserved through evolution and is crucial during embryonic development.

BDNF regulates Rab11-mediated recycling endosome dynamics to induce dendritic branching.

Dendritic arborization of neurons is regulated by brain-derived neurotrophic factor (BDNF) together with its receptor, TrkB. Endocytosis is required for dendritic branching and regulates TrkB signaling, but how postendocytic trafficking determines the neuronal response to BDNF is not well understood. The monomeric GTPase Rab11 regulates the dynamics of recycling endosomes and local delivery of receptors to specific dendritic compartments. We investigated whether Rab11-dependent trafficking of TrkB in dendrites regulates BDNF-induced dendritic branching in rat hippocampal neurons. We report that TrkB in dendrites is a cargo for Rab11 endosomes and that both Rab11 and its effector, MyoVb, are required for BDNF/TrkB-induced dendritic branching. In addition, BDNF induces the accumulation of Rab11-positive endosomes and GTP-bound Rab11 in dendrites and the expression of a constitutively active mutant of Rab11 is sufficient to increase dendritic branching by increasing TrkB localization in dendrites and enhancing sensitization to endogenous BDNF. We propose that Rab11-dependent dendritic recycling provides a mechanism to retain TrkB in dendrites and to increase local signaling to regulate arborization.

An autocrine Wnt5a-Ror signaling loop mediates sympathetic target innervation.

During nervous system development, axon branching at nerve terminals is an essential step in the formation of functional connections between neurons and target cells. It is known that target tissues exert control of terminal arborization through secretion of trophic factors. However, whether the in-growing axons themselves produce diffusible cues to instruct target innervation remains unclear. Here, we use conditional mutant mice to show that Wnt5a derived from sympathetic neurons is required for their target innervation in vivo. Conditional deletion of Wnt5a resulted in specific deficits in the extension and arborization of sympathetic fibers in their final target fields, while no defects were observed in the overall tissue patterning, proliferation, migration or differentiation of neuronal progenitors. Using compartmentalized neuronal cultures, we further demonstrate that the Ror receptor tyrosine kinases are required locally in sympathetic axons to mediate Wnt5a-dependent branching. Thus, our study suggests an autocrine Wnt5a-Ror signaling pathway that directs sympathetic axon branching during target innervation.

Wnt5a is necessary for normal kidney development in zebrafish and mice.

BACKGROUND: Wnt5a is important for the development of various organs and postnatal cellular function. Little is known, however, about the role of Wnt5a in kidney development, although WNT5A mutations were identified in patients with Robinow syndrome, a genetic disease which includes developmental defects in kidneys. Our goal in this study was to determine the role of Wnt5a in kidney development. METHODS: Whole-mount in situ hybridization was used to establish the expression pattern of Wnt5a during kidney development. Zebrafish with wnt5a knockdown and Wnt5a global knockout mice were used to identify kidney phenotypes. RESULTS: In zebrafish, wnt5a knockdown resulted in glomerular cyst formation and dilated renal tubules. In mice, Wnt5a global knockout resulted in pleiotropic, but severe, kidney phenotypes, including agenesis, fused kidney, hydronephrosis and duplex kidney/ureter. CONCLUSIONS: Our data demonstrated the important role of Wnt5a in kidney development. Disrupted Wnt5a resulted in kidney cysts in zebrafish and pleiotropic abnormal kidney development in mice.