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Zebrafish larvae, especially gene-specific mutants and transgenic lines, are increasingly used to study vertebrate skeletal development and human pathologies such as osteoporosis, osteopetrosis and osteoarthritis. Probiotics have been recognized in recent years as a prophylactic treatment for various bone health issues in humans. Here, we present two new zebrafish transgenic lines containing the coding sequences for fluorescent proteins inserted into the endogenous genes for sp7 and col10a1a with larvae displaying fluorescence in developing osteoblasts and the bone extracellular matrix (mineralized or non-mineralized), respectively. Furthermore, we use these transgenic lines to show that exposure to two different probiotics, Bacillus subtilis and Lactococcus lactis, leads to an increase in osteoblast formation and bone matrix growth and mineralization. Gene expression analysis revealed the effect of the probiotics, particularly Bacillus subtilis, in modulating several skeletal development genes, such as runx2, sp7, spp1 and col10a1a, further supporting their ability to improve bone health. Bacillus subtilis was the more potent probiotic able to significantly reverse the inhibition of bone matrix formation when larvae were exposed to a BMP inhibitor (LDN212854). [ABSTRACT FROM AUTHOR]

Background: Scales are mineralised exoskeletal structures that are part of the dermal skeleton. Scales have been mostly lost during evolution of terrestrial vertebrates whilst bony fish have retained a mineralised dermal skeleton in the form of fin rays and scales. Each scale is a mineralised collagen plate that is decorated with both matrix-building and resorbing cells. When removed, an ontogenetic scale is quickly replaced following differentiation of the scale pocket-lining cells that regenerate a scale. Processes promoting de novo matrix formation and mineralisation initiated during scale regeneration are poorly understood. Therefore, we performed transcriptomic analysis to determine gene networks and their pathways involved in dermal scale regeneration. Results: We defined the transcriptomic profiles of ontogenetic and regenerating scales of zebrafish and identified 604 differentially expressed genes (DEGs). These were enriched for extracellular matrix, ossification, and cell adhesion pathways, but not in enamel or dentin formation processes indicating that scales are reminiscent to bone. Hypergeometric tests involving monogenetic skeletal disorders showed that DEGs were strongly enriched for human orthologues that are mutated in low bone mass and abnormal bone mineralisation diseases (P< 2× 10−3). The DEGs were also enriched for human orthologues associated with polygenetic skeletal traits, including height (P< 6× 10−4), and estimated bone mineral density (eBMD, P< 2× 10−5). Zebrafish mutants of two human orthologues that were robustly associated with height (COL11A2, P=6× 10−24) or eBMD (SPP1, P=6× 10−20) showed both exo- and endo- skeletal abnormalities as predicted by our genetic association analyses; col11a2Y228X/Y228X mutants showed exoskeletal and endoskeletal features consistent with abnormal growth, whereas spp1P160X/P160X mutants predominantly showed mineralisation defects. Conclusion: We show that scales have a strong osteogenic expression profile comparable to other elements of the dermal skeleton, enriched in genes that favour collagen matrix growth. Despite the many differences between scale and endoskeletal developmental processes, we also show that zebrafish scales express an evolutionarily conserved sub-population of genes that are relevant to human skeletal disease. [ABSTRACT FROM AUTHOR]

The impregnation of biominerals into the extracellular matrix of living organisms, a process termed biomineralization, gives rise to diverse mineralized (or calcified) tissues in vertebrates. Preservation of mineralized tissues in the fossil record has provided insights into the evolutionary history of vertebrates and their skeletons. However, current understanding of the vertebrate skeleton and of the processes underlying its formation is biased towards biomedical models such as the tetrapods mouse and chick. Chondrichthyans (sharks, skates, rays, and chimaeras) and osteichthyans are the only vertebrate groups with extant (living) representatives that have a mineralized skeleton, but the basal phylogenetic position of chondrichthyans could potentially offer unique insights into skeletal evolution. For example, bone is a vertebrate novelty, but the internal supporting skeleton (endoskeleton) of extant chondrichthyans is commonly described as lacking bone. The molecular and developmental basis for this assertion is yet to be tested. Subperichondral tissues in the endoskeleton of some chondrichthyans display mineralization patterns and histological and molecular features of bone, thereby challenging the notion that extant chondrichthyans lack endoskeletal bone. Additionally, the chondrichthyan endoskeleton demonstrates some unique features and others that are potentially homologous with other vertebrates, including a polygonal mineralization pattern, a trabecular mineralization pattern, and an unconstricted perichordal sheath. Because of the basal phylogenetic position of chondrichthyans among all other extant vertebrates with a mineralized skeleton, developmental and molecular studies of chondrichthyans are critical to flesh out the evolution of vertebrate skeletal tissues, but only a handful of such studies have been carried out to date. This review discusses morphological and molecular features of chondrichthyan endoskeletal tissues and cell types, ultimately emphasizing how comparative embryology and transcriptomics can reveal homology of mineralized skeletal tissues (and their cell types) between chondrichthyans and other vertebrates. [ABSTRACT FROM AUTHOR]

Hypertrophic chondrocytes and their specific marker, the type X collagen gene (Col10a1), are critical components of endochondral bone formation during skeletal development. We previously found that Runx2 is an indispensable mouse Col10a1 gene regulator and identified many other transcription factors (TFs) that potentially interact with the 150-bp Col10a1 cis-enhancer. However, the roles of these candidate TFs in Col10a1 expression and chondrocyte hypertrophy have not been elucidated. Here, we focus on 32 candidate TFs recently identified by analyzing the 150-bp Col10a1 enhancer using the transcription factor affinity prediction (TRAP) program. We found that 12 TFs (Hoxa3, Lsx, Evx2, Dlx5, S8, Pax2, Egr2, Mef2a, Barhl2, GKlf, Sox17, and Crx) were significantly upregulated and four TFs (Lhx4, Tbx5, Mef2c, and Hb9) were significantly downregulated in hypertrophic MCT cells, which show upregulation of Col10a1 expression. Most of the differential expression pattern of these TFs conformed with the results obtained from ATDC5 cell model and primary mouse chondrocytes. Notably, Tbx5 was downregulated upon Col10a1 upregulation, overexpression of Tbx5 decreased Col10a1 expression, and knock-down of Tbx5 increased Col10a1 expression in hypertrophic chondrocytes, suggesting that Tbx5 is a negative regulator of Col10a1. We further generated a stable Tbx5 -overexpressing ATDC5 cell line and ColX-Tbx5 transgenic mice driven by Col10a1 -specific enhancers and promoters. Tbx5 overexpression decreased Col10a1 expression in ATDC5 cells cultured as early as day 7 and in limb tissue on post-natal day 1. Slightly weaker alkaline phosphatase staining was also observed in cell culture on day 7 and in limb digits on embryonic day 17.5, indicating mildly delayed ossification. Further characterization of these candidate Col10a1 transcriptional regulators could help identify novel therapeutic targets for skeletal diseases associated with abnormal chondrocyte hypertrophy. [ABSTRACT FROM AUTHOR]

When describing the architecture and ultrastructure of animal skeletons, introductory biology, anatomy and histology textbooks typically focus on the few bone and cartilage types prevalent in humans. In reality, cartilage and bone are far more diverse in the animal kingdom, particularly within fishes (Chondrichthyes and Actinopterygii), where cartilage and bone types are characterized by features that are anomalous or even pathological in human skeletons. This review discusses the curious and complex architectures of shark and ray tessellated cartilage, highlighting similarities and differences with their mammalian skeletal tissue counterparts. By synthesizing older anatomical literature with recent high‐resolution structural and materials characterization work, this review frames emerging pictures of form–function relationships in this tissue and of the evolution and true diversity of cartilage and bone. [ABSTRACT FROM AUTHOR]

Gene expression in extant animals might reveal how skeletal cells have evolved over the past 500 million years. The cells that make up cartilage (chondrocytes) and bone (osteoblasts) express many of the same genes, but they also have important molecular differences that allow us to distinguish them as separate cell types. For example, traditional studies of later‐diverged vertebrates, such as mouse and chick, defined the genes Col2a1 and sex‐determining region Y‐box 9 as cartilage‐specific. However, recent studies have shown that osteoblasts of earlier‐diverged vertebrates, such as frog, gar, and zebrafish, express these 'chondrogenic' markers. In this review, we examine the resulting hypothesis that chondrogenic gene expression became repressed in osteoblasts over evolutionary time. The amphibian is an underexplored skeletal model that is uniquely positioned to address this hypothesis, especially given that it diverged when life transitioned from water to land. Given the relationship between phylogeny and ontogeny, a novel discovery for skeletal cell evolution might bolster our understanding of skeletal cell development. [ABSTRACT FROM AUTHOR]

Oxygen is a key regulator of both development and homeostasis and a promising candidate to bridge the influence of the environment and the evolution of new traits. To clarify the various ways in which oxygen may modulate embryogenesis, its effects are reviewed at distinct organizational levels. First, the role of pathways that sense dioxygen levels and reactive oxygen species are reviewed. Then, the effects of microenvironmental oxygen on metabolism, stemness, and differentiation throughout embryogenesis are discussed. Last, the interplay between ecology and development are reexamined with a focus on the evolution of tetrapods, including during the emergence of a novel mechanism that shapes amniote limbs—interdigital cell death. Both genetic and environmental components work together during the formation of organisms, highlighting the importance of a multidisciplinary approach for understanding the evolution of new traits. [ABSTRACT FROM AUTHOR]

Age-related muscle weakness and loss of muscle mass (sarcopenia) is a universal problem in the elderly. Our previous studies indicate that alpha motor neurons (α-MNs) play a critical role in this process. The goal of the current study is to uncover changes in the aging spinal cord that contribute to loss of innervation and the downstream degenerative processes that occur in skeletal muscle. The number of α-MNs is decreased in the spinal cord of wildtype mice during aging, beginning in middle age and reaching a 41% loss by 27 months of age. There is evidence for age-related loss of myelin and mild inflammation, including astrocyte and microglia activation and an increase in levels of sICAM-1. We identified changes in metabolites consistent with compromised neuronal viability, such as reduced levels of N-acetyl-aspartate. Cleaved caspase-3 is more abundant in spinal cord from old mice, suggesting that apoptosis contributes to neuronal loss. RNA-seq analysis revealed changes in the expression of a number of genes in spinal cord from old mice, in particular genes encoding extracellular matrix components (ECM) and a 172-fold increase in MMP-12 expression. Furthermore, blood-spinal cord barrier (BSCB) permeability is increased in old mice, which may contribute to alterations in spinal cord homeostasis and exacerbate neuronal distress. Together, these data show for the first time that the spinal cord undergoes significant changes during aging, including progressive α-MNs loss that is associated with low-grade inflammation, apoptosis, changes in ECM, myelination, and vascular permeability. [ABSTRACT FROM AUTHOR]

HIV-associated sensory neuropathy (HIV-SN) is a debilitating neurological complication of HIV infection potentiated by the antiretroviral drug stavudine. While stavudine is no longer used, HIV-SN now affects around 15% of HIV+ Indonesians. Here, we investigate whether polymorphisms within the P2X-block (P2X4R, P2X7R, CAMKK2) and/or ANAPC5 mark susceptibility to HIV-SN in this setting. As polymorphisms in these genes associated with HIV-SN in African HIV patients receiving stavudine, the comparison can identify mechanisms independent of stavudine. HIV patients who had never used stavudine (n = 202) attending clinics in Jakarta were screened for neuropathy using the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen. Open-array technology was used to type 48 polymorphisms spanning the four genes. Haplotypes were derived for each gene using fastPHASE. Haplogroups were constructed with median-joining methods. Multivariable models optimally predicting HIV-SN were based on factors achieving p < 0.2 in bivariate analyses. Minor alleles of three co-inherited polymorphisms in CAMKK2 (rs7975295*C, rs1560568*A, rs1132780*T) associated with a reduced prevalence of HIV-SN individually and after adjusting for lower CD4 T cell count and viremia (p = 0.0002, pseudo R2 = 0.11). The optimal model for haplotypes linked HIV-SN with viremia and lower current CD4 T cell count, plus CAMKK2 haplotypes 6 and 11 and P2X7R haplotypes 2 and 12 (p = 0.0002; pseudo R2 = 0.11). CAMKK2 haplogroup A (includes 16 haplotypes and all instances of rs7975295*C, rs1560568*A, rs1132780*T) associated with reduced rates of HIV-SN (p = 0.02, OR = 0.43 CI = 0.21–0.88). These findings support a protective role for these three alleles, suggesting a role in the pathogenesis of HIV-SN that is independent of stavudine. [ABSTRACT FROM AUTHOR]

MEIStranscription factors are key regulators ofembryonic development and cancer. Research on MEIS genes in the embryo and in stem cell systems has revealed novel and surprisingmechanisms bywhich these proteins control gene expression. This Primer summarizes recent findings aboutMEIS protein activity and regulation in development, and discusses new insights into the role ofMEIS genes in disease, focusing on the pathogenesis of solid cancers. [ABSTRACT FROM AUTHOR]

Amputation of a sensory peripheral nerve induces severe anatomical and functional changes along the afferent pathway as well as perception alterations and neuropathic pain. In previous studies we showed that electrical stimulation applied to a transected infraorbital nerve protects the somatosensory cortex from the above-mentioned sensory deprivation-related changes. In the present study we focus on the initial tract of the somatosensory pathway and we investigate the way weak electrical stimulation modulates the neuroprotective-neuroregenerative and functional processes of trigeminal ganglia primary sensory neurons by studying the expression of neurotrophins (NTFs) and Glia-Derived Neurotrophic Factors (GDNFs) receptors. Neurostimulation was applied to the proximal stump of a transected left infraorbitary nerve using a neuroprosthetic micro-device 12 h/day for 4 weeks in freely behaving rats. Neurons were studied by in situ hybridization and immunohistochemistry against RET (proto-oncogene tyrosine kinase "rearranged during transfection"), tropomyosin-related kinases (TrkA, TrkB, TrkC) receptors and IB4 (Isolectin B4 from Griffonia simplicifolia). Intra-group (left vs. right ganglia) and inter-group comparisons (between Control, Axotomization and Stimulation-after-axotomization groups) were performed using the mean percentage change of the number of positive cells per section [100∗(left–right)/right)]. Intra-group differences were studied by paired t -tests. For inter-group comparisons ANOVA test followed by post hoc LSD test (when P < 0.05) were used. Significance level (α) was set to 0.05 in all cases. Results showed that (i) neurostimulation has heterogeneous effects on primary nociceptive and mechanoceptive/proprioceptive neurons; (ii) neurostimulation affects RET-expressing small and large neurons which include thermo-nociceptors and mechanoceptors, as well as on the IB4- and TrkB-positive populations, which mainly correspond to non-peptidergic thermo-nociceptive cells and mechanoceptors respectively. Our results suggest (i) electrical stimulation differentially affects modality-specific primary sensory neurons (ii) artificial input mainly acts on specific nociceptive and mechanoceptive neurons (iii) neuroprosthetic stimulation could be used to modulate peripheral nerve injuries-induced neuropathic pain. These could have important functional implications in both, the design of effective clinical neurostimulation-based protocols and the development of neuroprosthetic devices, controlling primary sensory neurons through selective neurostimulation. [ABSTRACT FROM AUTHOR]

Key points: An ex vivo preparation was developed to record from single sensory fibres innervating the glabrous skin of the mouse forepaw.The density of mechanoreceptor innervation of the forepaw glabrous skin was found to be three times higher than that of hindpaw glabrous skin.Rapidly adapting mechanoreceptors that innervate Meissner's corpuscles were severalfold more responsive to slowly moving stimuli in the forepaw compared to those innervating hindpaw skin.We found a distinct group of small hairs in the centre of the mouse hindpaw glabrous skin that were exclusively innervated by directionally sensitive D‐hair receptors.The directional sensitivity, but not the end‐organ anatomy, were the opposite to D‐hair receptors in the hairy skin.Glabrous skin hairs in the hindpaw are not ubiquitous in rodents, but occur in African and North American species that diverged more than 65 million years ago. Rodents use their forepaws to actively interact with their tactile environment. Studies on the physiology and anatomy of glabrous skin that makes up the majority of the forepaw are almost non‐existent in the mouse. Here we developed a preparation to record from single sensory fibres of the forepaw and compared anatomical and physiological receptor properties to those of the hindpaw glabrous and hairy skin. We found that the mouse forepaw skin is equipped with a very high density of mechanoreceptors; >3 times more than hindpaw glabrous skin. In addition, rapidly adapting mechanoreceptors that innervate Meissner's corpuscles of the forepaw were severalfold more sensitive to slowly moving mechanical stimuli compared to their counterparts in the hindpaw glabrous skin. All other mechanoreceptor types as well as myelinated nociceptors had physiological properties that were invariant regardless of which skin area they occupied. We discovered a novel D‐hair receptor innervating a small group of hairs in the middle of the hindpaw glabrous skin in mice. These glabrous skin D‐hair receptors were direction sensitive albeit with an orientation sensitivity opposite to that described for hairy skin D‐hair receptors. Glabrous skin hairs do not occur in all rodents, but are present in North American and African rodent species that diverged more than 65 million years ago. The function of these specialized hairs is unknown, but they are nevertheless evolutionarily very ancient. Our study reveals novel physiological specializations of mechanoreceptors in the glabrous skin that likely evolved to facilitate tactile exploration. Key points: An ex vivo preparation was developed to record from single sensory fibres innervating the glabrous skin of the mouse forepaw.The density of mechanoreceptor innervation of the forepaw glabrous skin was found to be three times higher than that of hindpaw glabrous skin.Rapidly adapting mechanoreceptors that innervate Meissner's corpuscles were severalfold more responsive to slowly moving stimuli in the forepaw compared to those innervating hindpaw skin.We found a distinct group of small hairs in the centre of the mouse hindpaw glabrous skin that were exclusively innervated by directionally sensitive D‐hair receptors.The directional sensitivity, but not the end‐organ anatomy, were the opposite to D‐hair receptors in the hairy skin.Glabrous skin hairs in the hindpaw are not ubiquitous in rodents, but occur in African and North American species that diverged more than 65 million years ago. [ABSTRACT FROM AUTHOR]

Noise-induced hearing loss (NIHL) is one of the major occupational disease that has influence on the quality of life of mining workers. Several reports suggest NIHL is attributed to noise exposure at workplace and approximately 16% of hearing loss is due to it. NIHL occurs as a result of exposure to high-level noise (>85 dB) in the workplace. Noise disrupts proteins present in the micromachinery of the ear that is required for mechano-electric transduction of sound waves. High-level noise exposure can lead to hearing impairment owing to mechanical and metabolic exhaustion in cochlea, the major organ responsible for resilience of sound. Several key proteins of cochlea include tectorial membrane, inner hair cells, outer hair cells, and stereocilia are damaged due to high-level noise exposure. Numerous studies conducted in animals have shown cochlear proteins involvement in NIHL, but the pertinent literature remains limited in humans. Detection of proteins and pathways perturbed within the micromachinery of the ear after excessive sound induction leads toward the early identification of hearing loss. The situation insisted to present this review as an update on cochlear proteins associated with NIHL after an extensive literature search using several electronic databases which help to understand the pathophysiology of NIHL. [ABSTRACT FROM AUTHOR]

Compared to other types of cells, neurons express the largest number of diverse mRNAs, including neuron-specific ones. This mRNA diversity is required for neuronal function, memory storage, maintenance and retrieval. Regulation of translation in neurons is very complicated and involves various proteins. Some proteins, implementing translational control in other cell types, are used by neurons for synaptic plasticity. In this review, we discuss the neuron-specific activity of four kinases: protein kinase R (PKR), PKR-like endoplasmic reticulum kinase (PERK), general control nonderepressible 2 kinase (GCN2), and heme-reguated eIF2α kinase (HRI), the substrate for which is α-subunit of eukaryotic initiation factor 2 (eIF2α). Phosphorylation of eIF2α is necessary for the cell during stress conditions, such as lack of amino acids, energy stress or viral infection. We propose that, during memory formation, neurons use some mechanisms similar to those involved in the cellular stress. The four eIF2α kinases regulate translation of certain mRNAs containing upstream open reading frames (uORFs). These mRNAs encode proteins involved in the processes of long-term potentiation (LTP) or long-term depression (LTD). The review examines some neuronal proteins for which translation regulation by eIF2 was suggested and checked experimentally. Of such proteins, we pay close attention to protein kinase Mζ which is involved in memory storage and regulated at the translational level. [ABSTRACT FROM AUTHOR]

Noxious stimuli cause pain by activating cutaneous nociceptors. The Aδ- and C-fibers of dorsal root ganglion (DRG) neurons convey the nociceptive signals to the laminae I-II of spinal cord. In the dorsal horn of spinal cord, the excitatory afferent synaptic transmission is regulated by the inhibitory neurotransmitter γ-aminobutyric acid and modulators such as opioid peptides released from the spinal interneurons, and by serotonin, norepinepherine and dopamine from the descending inhibitory system. In contrast to the accumulated evidence for these central inhibitors and their neural circuits in the dorsal spinal cord, the knowledge about the endogenous suppressive mechanisms in nociceptive DRG neurons remains very limited. In this review, we summarize our recent findings of the presynaptic suppressive mechanisms in nociceptive neurons, the BNP/NPR-A/PKG/BKCa channel pathway, the FSTL1/α1Na-K ATPase pathway and the activin C/ERK pathway. These endogenous suppressive systems in the mechanoheat nociceptors may also contribute differentially to the mechanisms of nerve injury-induced neuropathic pain or inflammation-induced pain. [ABSTRACT FROM AUTHOR]

ABSTRACT Famous for its blind cavefish and Darwin's finches, Latin America is home to some of the richest biodiversity hotspots of our planet. The Latin American fauna and flora inspired and captivated naturalists from the nineteenth and twentieth centuries, including such notable pioneers such as Fritz Müller, Florentino Ameghino, and Léon Croizat who made a significant contribution to the study of embryology and evolutionary thinking. But, what are the historical and present contributions of the Latin American scientific community to Evo-Devo? Here, we provide the first comprehensive overview of the Evo-Devo laboratories based in Latin America and describe current lines of research based on endemic species, focusing on body plans and patterning, systematics, physiology, computational modeling approaches, ecology, and domestication. Literature searches reveal that Evo-Devo in Latin America is still in its early days; while showing encouraging indicators of productivity, it has not stabilized yet, because it relies on few and sparsely distributed laboratories. Coping with the rapid changes in national scientific policies and contributing to solve social and health issues specific to each region are among the main challenges faced by Latin American researchers. The 2015 inaugural meeting of the Pan-American Society for Evolutionary Developmental Biology played a pivotal role in bringing together Latin American researchers eager to initiate and consolidate regional and worldwide collaborative networks. Such networks will undoubtedly advance research on the extremely high genetic and phenotypic biodiversity of Latin America, bound to be an almost infinite source of amazement and fascinating findings for the Evo-Devo community. [ABSTRACT FROM AUTHOR]

The fundamental role of Na,K-ATPase in eukaryotic cells calls for complex and efficient regulation of its activity. Besides alterations in gene expression and trafficking, kinetic properties of the pump are modulated by reversible association with single span membrane proteins, the FXYDs. Seven members of the family are expressed in a tissue-specific manner, affecting pump kinetics in all possible permutations. This mini-review focuses on functional properties of FXYD2 studied in transfected cells, and on noteworthy and unexpected phenotypes discovered in a Fxyd2-/- mouse. FXYD2, the gamma subunit, reduces activity of Na,K-ATPase either by decreasing affinity for Na+, or reducing Vmax. FXYD2 mRNA splicing and editing provide another layer for regulation of Na,K-ATPase. In kidney of knockouts, there was elevated activity for Na,K-ATPase and for NCC and NKCC2 apical sodium transporters. That should lead to sodium retention and hypertension, however, the mice were in sodium balance and normotensive. Adult Fxyd2-/- mice also exhibited a mild pancreatic phenotype with enhanced glucose tolerance, elevation of circulating insulin, but no insulin resistance. There was an increase in beta cell proliferation and beta cell mass that correlated with activation of the PI3K-Akt pathway. The Fxyd2-/- mice are thus in a highly desirable state: the animals are resistant to Na+ retention, and showed improved glucose control, i.e., they display favorable metabolic adaptations to protect against development of salt-sensitive hypertension and diabetes. Investigation of the mechanisms of these adaptations in the mouse has the potential to unveil a novel therapeutic FXYD2-dependent strategy. [ABSTRACT FROM AUTHOR]

ABSTRACT Sensory receptors in the vestibular system (hair cells) encode head movements and drive central motor reflexes that control gaze, body movements, and body orientation. In mammals, type I and II vestibular hair cells are defined by their shape, contacts with vestibular afferent nerves, and membrane conductance. Here we describe unique morphological features of type II vestibular hair cells in mature rodents (mice and gerbils) and bats. These features are cytoplasmic processes that extend laterally from the hair cell base and project under type I hair cells. Closer analysis of adult mouse utricles demonstrated that the basolateral processes of type II hair cells vary in shape, size, and branching, with the longest processes extending three to four hair cell widths. The hair cell basolateral processes synapse upon vestibular afferent nerves and receive inputs from vestibular efferent nerves. Furthermore, some basolateral processes make physical contacts with the processes of other type II hair cells, forming some sort of network among type II hair cells. Basolateral processes are rare in perinatal mice and do not attain their mature form until 3-6 weeks of age. These observations demonstrate that basolateral processes are significant signaling regions of type II vestibular hair cells and suggest that type II hair cells may directly communicate with each other, which has not been described in vertebrates. J. Comp. Neurol. 522:3141-3159, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Neurotrauma assumes an instant or delayed disconnection of axons (axotomy), which affects not only neurons, but surrounding glia as well. Not only mechanically injured glia near the site of disconnection, especially transection, is subjected to the damage, but also glia that is remote from the lesion site. Glial cells, which surround the neuronal body, in turn, support neuron survival, so there is a mutual protection between neuron and glia. Calcium signaling is a central mediator of all post-axotomy events, both in neuron and glia, playing a critical role in their survival/regeneration or death/degeneration. The involvement of calcium in post-axotomy survival of the remote, mechanically intact glia is poorly studied. The purpose of this review is to sum up the calcium-involving mechanisms in responses of neurons and glial cells to axotomy to show their importance and to give some suggestions for future research of remote glia in this context. [ABSTRACT FROM AUTHOR]

Biomineralization is the process by which organisms produce hard inorganic matter from soft tissues with outstanding control of mineral deposition in time and space. For this purpose, organisms deploy a sophisticated "toolkit" that has resulted in significant evolutionary innovations, for which calcium phosphate (CaP) is the biomineral selected for the skeleton of vertebrates. While CaP mineral formation in aqueous media can be investigated by studying thermodynamics and kinetics of phase transitions in supersaturated solutions, biogenic mineralization requires coping with the inherent complexity of biological systems. This mainly includes compartmentalization and homeostatic processes used by organisms to regulate key physiological factors, including temperature, pH and ion concentration. A detailed analysis of the literature shows the emergence of two main views describing the mechanism of CaP biomineralization. The first one, more dedicated to the study of in vivo systems and supported by researchers in physiology, often involves matrix vesicles (MVs). The second one, more investigated by the physicochemistry community, involves collagen intrafibrillar mineralization particularly through in vitro acellular models. Herein, we show that there is an obvious need in the biological systems to control both where and when the mineral forms through an in-depth survey of the mechanism of CaP mineralization. This necessity could gather both communities of physiologists and physicochemists under a common interest for an enzymatic approach to better describe CaP biomineralization. Both homogeneous and heterogeneous enzymatic catalyses are conceivable for these systems, and a few preliminary promising results on CaP mineralization for both types of enzymatic catalysis are reported in this work. Through them, we aim to describe the relevance of our point of view and the likely findings that could be obtained when adding an enzymatic approach to the already rich and creative research field dealing with CaP mineralization. This complementary approach could lead to a better understanding of the biomineralization mechanism and inspire the biomimetic design of new materials. [ABSTRACT FROM AUTHOR]

Prolonged use of opioids can cause opioid-induced hyperalgesia (OIH). The impact of alternative splicing on OIH remains partially characterized. A study of the absolute and relative modes of action of alternative splicing further the understanding of the molecular mechanisms underlying OIH. Differential absolute and relative isoform profiles were detected in the trigeminal ganglia and nucleus accumbens of mice presenting OIH behaviors elicited by chronic morphine administration relative to control mice. Genes that participate in glutamatergic synapse (e.g., Grip1, Grin1, Wnk3), myelin protein processes (e.g., Mbp, Mpz), and axon guidance presented absolute and relative splicing associated with OIH. Splicing of genes in the gonadotropin-releasing hormone receptor pathway was detected in the nucleus accumbens while splicing in the vascular endothelial growth factor, endogenous cannabinoid signaling, circadian clock system, and metabotropic glutamate receptor pathways was detected in the trigeminal ganglia. A notable finding was the prevalence of alternatively spliced transcription factors and regulators (e.g., Ciart, Ablim2, Pbx1, Arntl2) in the trigeminal ganglia. Insights into the nociceptive and antinociceptive modulatory action of Hnrnpk were gained. The results from our study highlight the impact of alternative splicing and transcriptional regulators on OIH and expose the need for isoform-level research to advance the understanding of morphine-associated hyperalgesia. [ABSTRACT FROM AUTHOR]

Jawed vertebrates (gnathostomes) have been the dominant lineage of deuterostomes for nearly three hundred fifty million years. Only a few lineages of jawless vertebrates remain in comparison. Composed of lampreys and hagfishes (cyclostomes), these jawless survivors are important systems for understanding the evolution of vertebrates. One focus of cyclostome research has been head skeleton development, as its evolution has been a driver of vertebrate morphological diversification. Recent work has identified hyaline-like cartilage in the oral cirri of the invertebrate chordate amphioxus, making cyclostomes critical for understanding the stepwise acquisition of vertebrate chondroid tissues. Our knowledge of cyclostome skeletogenesis, however, has lagged behind gnathostomes due to the difficulty of manipulating lamprey and hagfish embryos. In this review, we discuss and compare the regulation and histogenesis of cyclostome and gnathostome skeletal tissues. We also survey differences in skeletal morphology that we see amongst cyclostomes, as few elements can be confidently homologized between them. A recurring theme is the heterogeneity of skeletal morphology amongst living vertebrates, despite conserved genetic regulation. Based on these comparisons, we suggest a model through which these mesenchymal connective tissues acquired distinct histologies and that histological flexibility in cartilage existed in the last common ancestor of modern vertebrates. [ABSTRACT FROM AUTHOR]

Mowat-Wilson Syndrome (MWS) (OMIM # 235730) is a rare disorder due to ZEB2 gene defects (heterozygous mutation or deletion). The ZEB2 gene is a widely expressed regulatory gene, extremely important for the proper prenatal development. MWS is characterized by a specific facial gestalt and multiple musculoskeletal, cardiac, gastrointestinal, and urogenital anomalies. The nervous system involvement is extensive and constitutes one of the main features in MWS, heavily affecting prognosis and life quality of affected individuals. This review aims to comprehensively organize and discuss the neurological and neurodevelopmental phenotype of MWS. First, we will describe the role of ZEB2 in the formation and development of the nervous system by reviewing the preclinical studies in this regard. ZEB2 regulates the neural crest cell differentiation and migration, as well as in the modulation of GABAergic transmission. This leads to different degrees of structural and functional impairment that have been explored and deepened by various authors over the years. Subsequently, the different neurological aspects of MWS (head and brain malformations, epilepsy, sleep disorders, and enteric and peripheral nervous system involvement, as well as developmental, cognitive, and behavioral features) will be faced one at a time and extensively examined from both a clinical and etiopathogenetic point of view, linking them to the ZEB2 related pathways. [ABSTRACT FROM AUTHOR]