Bers-ERK Schwann Cells Coordinate Nerve Regeneration

In this issue of Neuron, Napoli et al. (2012) demonstrate that elevated ERK/MAPK signaling in Schwann cells is a crucial trigger for Schwann cell dedifferentiation in vivo. Moreover, the authors show that dedifferentiated Schwann cells have the potential to coordinate much of the peripheral nerve response to injury

Different Signaling Pathways Mediate Regenerative versus Developmental Sensory Axon Growth

Recent advances in defining neurotrophin signaling mediators have provided insights into the signal transduction mechanisms that underlie axon growth. Evidence is accumulating that major Trk effectors regulate the morphological development of embryonic peripheral neurons. Less is known about signaling related to the robust axon extension that follows peripheral axotomy of adult neurons. Regenerative axon growth can be mimicked in vitro by a "conditioning" lesion performed 2 weeks before culture (Smith and Skene, 1997). Previous work has implicated both neurotrophins and cytokines in this response. Because signal transduction mediators of both of these families of growth factors are well characterized, we have compared the role of neurotrophin and cytokine signaling in developmental versus regenerative sensory axon growth. Chemical inhibitors were administrated to embryonic and axotomized sensory neurons in vitro to block the activation of Erk kinase (MEK)-extracellular signal-regulated kinase (ERK), phosphatidylinositol-3 kinase (PI3-K), and janus kinase (JAK) signaling. As expected, both MEK and PI3-K inhibition blocked axon growth from both naive and NGF-stimulated embryonic day 13 sensory neurons, whereas inhibition of JAK phosphorylation had no effect. In contrast, neither MEK nor PI3-K inhibitors blocked elongation of adult sensory neurons after a conditioning lesion. However, the addition of a JAK2 inhibitor prevented the regenerative axon response. Consistent with these pharmacological results, the percentage of neurons showing intense nuclear signal transducers and activators of transcription 3 phosphorylation after a conditioning lesion was markedly increased compared with controls. These observations demonstrate that the signaling mediators that underlie regenerative axon growth are distinct from those used during development and suggest that cytokine signaling may be critical to peripheral nervous system regeneration

Functions of GSK-3 Signaling in Development of the Nervous System

Glycogen synthase kinase-3 (GSK-3) is central to multiple intracellular pathways including those activated by Wnt/β-catenin, Sonic Hedgehog, Notch, growth factor/RTK, and G protein-coupled receptor signals. All of these signals importantly contribute to neural development. Early attention on GSK-3 signaling in neural development centered on the regulation of neuronal polarity using in vitro paradigms. However, recent creation of appropriate genetic models has demonstrated the importance of GSK-3 to multiple aspects of neural development including neural progenitor self-renewal, neurogenesis, neuronal migration, neural differentiation, and synaptic development

“Runx”ing towards Sensory Differentiation

Somatosensory stimuli are encoded by molecularly and anatomically diverse classes of dorsal root ganglia (DRG) neurons. In this issue of Neuron, three papers demonstrate that the Runx transcription factors, Runx1 and Runx3, respectively regulate the molecular identities and spinal terminations of TrkA+ nociceptive neurons and TrkC+ proprioceptive neurons. These findings emphasize the importance of intrinsic genetic programs in generating the diversity of DRG neurons and specifying the circuits into which they incorporate

Pilot evaluation of the Text4Baby mobile health program

Background Mobile phone technologies for health promotion and disease prevention have evolved rapidly, but few studies have tested the efficacy of mobile health in full-fledged programs. Text4baby is an example of mobile health based on behavioral theory, and it delivers text messages to traditionally underserved pregnant women and new mothers to change their health, health care beliefs, practices, and behaviors in order to improve clinical outcomes. The purpose of this pilot evaluation study is to assess the efficacy of this text messaging campaign. Methods We conducted a randomized pilot evaluation study. All participants were pregnant women first presenting for care at the Fairfax County, Virginia Health Department. We randomized participants to enroll in text4baby and receive usual health care (intervention), or continue simply to receive usual care (control). We then conducted a 24-item survey by telephone of attitudes and behaviors related to text4baby. We surveyed participants at baseline, before text4baby was delivered to the intervention group, and at follow-up at approximately 28 weeks of baby’s gestational age. Results We completed 123 baseline interviews in English and in Spanish. Overall, the sample was predominantly of Hispanic origin (79.7%) with an average age of 27.6 years. We completed 90 follow-up interviews, and achieved a 73% retention rate. We used a logistic generalized estimating equation model to evaluate intervention effects on measured outcomes. We found a significant effect of text4baby intervention exposure on increased agreement with the attitude statement “I am prepared to be a new mother” (OR = 2.73, CI = 1.04, 7.18, p = 0.042) between baseline and follow-up. For those who had attained a high school education or greater, we observed a significantly higher overall agreement to attitudes against alcohol consumption during pregnancy (OR = 2.80, CI = 1.13, 6.90, p = 0.026). We also observed a significant improvement of attitudes toward alcohol consumption from baseline to follow-up (OR = 3.57, CI = 1.13 – 11.24, p = 0.029). Conclusions This pilot study is the first randomized evaluation of text4baby. It is a promising program in that exposure to the text messages was associated with changes in specific beliefs targeted by the messages

Taking Off the SOCS: Cytokine Signaling Spurs Regeneration

Strategies to improve function after CNS injuries must contend with the failure of axons to regrow after transection in adult mammals. In this issue of Neuron, Smith et al. provide an important advance by demonstrating that SOCS3 acts as a key negative regulator of adult optic nerve regeneration

Raf and Akt Mediate Distinct Aspects of Sensory Axon Growth

AbstractNerve growth factor (NGF) induces dramatic axon growth from responsive embryonic peripheral neurons. However, the roles of the various NGF-triggered signaling cascades in determining specific axon morphological features remain unknown. Here, we transfected activated and inhibitory mutants of Trk effectors into sensory neurons lacking the proapoptotic protein Bax. This allowed axon growth to be studied in the absence of NGF, enabling us to observe the contributions of individual signaling mediators. While Ras was both necessary and sufficient for NGF-stimulated axon growth, the Ras effectors Raf and Akt induced distinct morphologies. Activated Raf-1 caused axon lengthening comparable to NGF, while active Akt increased axon caliber and branching. Our results suggest that the different Trk effector pathways mediate distinct morphological aspects of developing neurons

ERK/MAPK Signaling Is Required for Pathway-Specific Striatal Motor Functions

The ERK/MAPK intracellular signaling pathway is hypothesized to be a key regulator of striatal activity via modulation of synaptic plasticity and gene transcription. However, prior investigations into striatal ERK/MAPK functions have yielded conflicting results. Further, these studies have not delineated the cell-type-specific roles of ERK/MAPK signaling due to the reliance on globally administered pharmacological ERK/MAPK inhibitors and the use of genetic models that only partially reduce total ERK/MAPK activity. Here, we generated mouse models in which ERK/MAPK signaling was completely abolished in each of the two distinct classes of medium spiny neurons (MSNs). ERK/MAPK deletion in D1R-MSNs (direct pathway) resulted in decreased locomotor behavior, reduced weight gain, and early postnatal lethality. In contrast, loss of ERK/MAPK signaling in D2R-MSNs (indirect pathway) resulted in a profound hyperlocomotor phenotype. ERK/MAPK-deficient D2R-MSNs exhibited a significant reduction in dendritic spine density, markedly suppressed electrical excitability, and suppression of activity-associated gene expression even after pharmacological stimulation. Our results demonstrate the importance of ERK/MAPK signaling in governing the motor functions of the striatal direct and indirect pathways. Our data further show a critical role for ERK in maintaining the excitability and plasticity of D2R-MSNs

Role of GSK3 Signaling in Neuronal Morphogenesis

Glycogen synthase kinase 3 (GSK3) is emerging as a key regulator of several aspects of neuronal morphogenesis including neuronal polarization, axon growth, and axon branching. Multiple signaling pathways have been identified that control neuronal polarization, including PI3K, Rho-GTPases, Par3/6, TSC–mTOR, and PKA–LKB1. However, how these pathways are coordinated is not clear. As GSK3 signaling exhibits crosstalk with each of these pathways it has the potential to integrate these polarity signals in the control neuronal polarization. After neurons establish polarity, GSK3 acts as an important signaling mediator in the regulation of axon extension and axon branching by transducing upstream signaling to reorganization of the axonal cytoskeleton, especially microtubules. Here we review the roles of GSK3 signaling in neuronal morphogenesis and discuss the underlying molecular mechanisms

BAX Is Required for Neuronal Death after Trophic Factor Deprivation and during Development

AbstractMembers of the BCL2-related family of proteins either promote or repress programmed cell death. BAX, a death-promoting member, heterodimerizes with multiple death-repressing molecules, suggesting that it could prove critical to cell death. We tested whether Bax is required for neuronal death by trophic factor deprivation and during development. Neonatal sympathetic neurons and facial motor neurons from Bax-deficient mice survived nerve growth factor deprivation and disconnection from their targets by axotomy, respectively. These salvaged neurons displayed remarkable soma atrophy and reduced elaboration of neurites; yet they responded to readdition of trophic factor with soma hypertrophy and enhanced neurite outgrowth. Bax-deficient superior cervical ganglia and facial nuclei possessed increased numbers of neurons. Our observations demonstrate that trophic factor deprivation–induced death of sympathetic and motor neurons depends on Bax