The role of intraspinal sensory neurons in the control of quadrupedal locomotion

From swimming to walking and flying, animals have evolved specific locomotor strategies to thrive in different habitats. All types of locomotion depend on integration of motor commands and sensory information to generate precise movements. Cerebrospinal fluid-contacting neurons (CSF-cN) constitute a vertebrate sensory system that monitors CSF composition and flow. In fish, CSF-cN modulate swimming activity in response to changes in pH and bending of the spinal cord, yet their role in higher vertebrates remains unknown. We used mouse genetics to study their function in quadrupedal locomotion and found that CSF-cN are directly integrated into spinal motor circuits by forming connections with motor neurons and premotor interneurons. Elimination of CSF-cN selectively perturbs the accuracy of foot placement required for skilled movements at the balance beam and horizontal ladder. These results identify an important role for mouse CSF-cN in adaptive motor control and indicate that this sensory system evolved a novel function from lower vertebrates to accommodate the biomechanical requirements of terrestrial locomotion.

MicroRNA-181b-2 and MicroRNA-21-1 Negatively Regulate NF-κB and IRF3-Mediated Innate Immune Responses via Targeting TRIF in Teleost

Upon recognition of bacterial or viral components by Toll-like receptors (TLRs), cells could be activated to induce a series of reactions to produce inflammatory cytokines, type I interferon (IFN), and IFN stimulating genes (ISG). MicroRNAs (miRNAs) are an important regulatory molecules that are widely involved in the regulatory networks of mammalian inflammation and immune responses; however, in lower vertebrates, the regulatory network of miRNA-mediated immune responses is poorly understood. Here, we report two miRNAs form Miichthys miiuy, namely, miR-181b-2 and miR-21-1, that play a negative role in host antiviral and antibacterial immunity. We found that miR-181b-2 and miR-21-1 are abundantly expressed in gram-negative bacteria, as well as RNA rhabdovirus infection. Inducible miR-181b-2 and miR-21-1 suppress the production of inflammatory cytokines and type I IFN by targeting TRIF, thereby avoiding excessive inflammation. We further revealed that miR-181b-2 and miR-21-1 modulate antibacterial and antiviral immunity through the TRIF-mediated NF-κB and IRF3 signaling pathways. The overall results indicate that miR-181b-2 and miR-21-1 act as negative feedback regulators and participate in host antibacterial and antiviral immune responses; this finding could provide information for a deeper understanding of the resistance of lower vertebrates to the invasion of pathogens and to avoidance of excessive immunity.

microRNA-20-1 and miR-101a suppress the NF-κB-mediated inflammation production by targeting TRAF6 in miiuy croaker

Upon recognition of the pathogen components by PRR (pattern recognition receptors), then the cells could be activated to produce inflammatory cytokines and type I interferons. The inflammation is tightly modulated by the host to prevent inappropriate inflammatory responses. MicroRNAs (miRNAs) are non-coding and small RNAs that can inhibit gene expression and participate in various biological functions, including maintaining a balanced immune response in the host. To maintain the balance of the immune response, these pathways are closely regulated by the host to prevent inappropriate reactions of the cells. However, in low vertebrates, the miRNA-mediated inflammatory response regulatory networks remain largely unknown. Here, we report that two miRNAs, miR-20-1 and miR-101a are identified as negative regulators in teleost inflammatory responses. Initially, we find that both miR-20-1 and miR-101a dramatically increased after lipopolysaccharide (LPS) stimulation and Vibrio harveyi infection. Upregulated miR-20-1 and miR-101a inhibit LPS-induced inflammatory cytokines production by targeting TNF receptor-associated factor 6 (TRAF6), thus avoiding excessive inflammation. Moreover, miR-20-1 and miR-101a regulate the inflammatory responses through the TRAF6-mediated nuclear factor kappa (NF-κB) signaling pathways. Collectively, these data indicate that miR-20-1 and miR-101a act as negative regulators through regulating the TRAF6-mediated NF-κB signaling pathway, and participate in the host antibacterial immune responses, which will provide new insight into the intricate networks of the host-pathogen interaction in the lower vertebrates.

Pain sensing neurons promote tissue regeneration in adult mice

Tissue repair after injury in adult mammals, usually results in scarring and loss of function in contrast to lower vertebrates such as the newt and zebrafish that regenerate. Understanding the regulatory processes that guide the outcome of tissue repair is therefore a concerning challenge for regenerative medicine. In multiple regenerative animal species, the nerve dependence of regeneration is well established, but the nature of the innervation required for tissue regeneration remains largely undefined. Using our model of induced adipose tissue regeneration in adult mice, we demonstrate here that nociceptive nerves promote regeneration and their removal impairs tissue regeneration. We also show that blocking the receptor for the nociceptive neuropeptide calcitonin gene-related peptide (CGRP) inhibits regeneration, whereas CGRP administration induces regeneration. These findings reveal that peptidergic nociceptive neurons are required for adult mice tissue regeneration.

Long noncoding RNA MIR2187HG suppresses TBK1-mediated antiviral signaling through deriving miR-2187-3p in teleost fish

Long non-coding RNAs (lncRNAs) function as microregulatory factors that influence gene expression after a variety of pathogenic infection, which have been extensively studied in the past few years. Although less attention has been paid to lncRNAs in lower vertebrates than in mammals, current studies reveals that lncRNAs plays a vital role in fish stimulated by pathogens. Here, we discovered a new lncRNA, termed as MIR2187HG, which can function as a precursor of a small RNA miR-2187-3p with regulatory functions in miiuy croaker ( Miichthys miiuy ). Upon Siniperca chuatsi rhabdovirus (SCRV) virus infection, the expression levels of MIR2187HG were remarkably enhanced. Elevated MIR2187HG expression can act as a pivotally negative regulator that participates in the innate immune response of teleost fish to inhibit the intracellular TANK-binding kinase 1 (TBK1)-mediated antiviral signaling pathways, which can effectively avoid excessive immunity. In addition, we found that the SCRV virus could also utilize MIR2187HG to enhance its own number. Our results not only provide evidence regarding the involvement of the lncRNAs in response to anti-viruses in fish, but also broaden our understanding of the function of lncRNAs as precursor miRNA in teleost fish for the first time. Importance: SCRV infection upregulates MIR2187HG levels, which in turn suppresses SCRV-triggered type I interferon production, thus promoting viral replication in miiuy croaker. Notably, MIR2187HG regulates the release of miR-2187-3p, and TBK1 is a target of miR-2187-3p. MIR2187HG could obtain the function from miR-2187-3p to inhibit TBK1 expression and subsequently modulate TBK1-mediated NF-κB and IRF3 signaling. The collective results suggest that the novel regulation mechanism of TBK1-mediated antiviral response during RNA viral infection was regulated by MIR2187HG. Therefore, a new regulation mechanism for lncRNAs to regulate antiviral immune responses in fish is proposed.

NFkB-signaling promotes glial reactivity and suppresses Müller glia-mediated neuron regeneration in the mammalian retina

Müller glia (MG) in mammalian retinas are incapable of regenerating neurons after damage, whereas the MG in lower vertebrates regenerate functional neurons. Identification networks that regulate MG-mediated regeneration is key to harnessing the regenerative potential of MG. Here we study how NFkB-signaling influences glial responses to damage and reprogramming of MG into neurons in the rodent retina. We find activation of NFkB and dynamic expression of NFkB-associated genes in MG after damage, however NFkB activity is inhibited by microglia ablation. Knockout of NFkB in MG suppressed the accumulation of immune cells after damage. Inhibition of NFkB following NMDA-damage significantly enhanced the reprogramming of Ascl1-overexpressing MG into neuron-like cells. scRNA-seq of retinal glia following inhibition of NFkB reveals coordination with signaling via TGFβ2 and suppression of NFI and Id transcription factors. Inhibition of Smad3 or Id transcription factors increased numbers of neuron-like cells produced by Ascl1-overexpressing MG. We conclude that NFkB is a key signaling hub that is activated in MG after damage, mediates the accumulation of immune cells, and suppresses the neurogenic potential of MG.

Functional Activity of Recombinant Forms of Amh and Synergistic Action with Fsh in European Sea Bass Ovary

Although anti-Müllerian hormone (AMH) has classically been correlated with the regression of Müllerian ducts in male mammals, involvement of this growth factor in other reproductive processes only recently come to light. Teleost is the only gnathostomes that lack Müllerian ducts despite having amh orthologous genes. In adult teleost gonads, Amh exerts a role in the early stages of germ cell development in both males and females. Mechanisms involving the interaction of Amh with gonadotropin- and growth factor-induced functions have been proposed, but our overall knowledge regarding Amh function in fish gonads remains modest. In this study, we report on Amh actions in the European sea bass ovary. Amh and type 2 Amh receptor (Amhr2) are present in granulosa and theca cells of both early and late-vitellogenic follicles and cannot be detected in previtellogenic ovaries. Using the Pichia pastoris system a recombinant sea bass Amh has been produced that is endogenously processed to generate a 12–15 kDa bioactive mature protein. Contrary to previous evidence in lower vertebrates, in explants of previtellogenic sea bass ovaries, mature Amh has a synergistic effect on steroidogenesis induced by the follicle-stimulating hormone (Fsh), increasing E2 and cyp19a1a levels.

Hypoxia promotes a perinatal-like progenitor state in the adult murine epicardium

The epicardium is a reservoir of progenitors that give rise to coronary vasculature and stroma during development and mediates cardiac vascular repair in lower vertebrates. However, its role as a source of progenitors in the adult mammalian heart remains unclear due to lack of clear lineage markers and single-cell culture systems to elucidate epicardial progeny cell fate. We found that in vivo exposure of mice to physiological hypoxia induced adult epicardial cells to re-enter the cell cycle and to express a subset of developmental genes. Multiplex transcriptional profiling revealed a lineage relationship between epicardial cells and smooth muscle, stromal, and endothelial fates, and that physiological hypoxia promoted an endothelial cell fate. In vitro analyses of purified epicardial cells showed that cell growth and subsequent differentiation is dependent upon hypoxia, and that resident epicardial cells retain progenitor identity in the adult mammalian heart with self-renewal and multilineage differentiation potential. These results point to a source of progenitor cells in the adult heart that can promote heart revascularization, providing an invaluable in vitro model for further studies.

Comparative genomic analysis of a naturally born serpentized pig reveals putative mutations related to limb and bone development

Background It is believed that natural selection acts on the phenotypical changes caused by mutations. Phenotypically, from fishes to amphibians to reptiles, the emergence of limbs greatly facilitates the landing of ancient vertebrates, but the causal mutations and evolutionary trajectory of this process remain unclear. Results We serendipitously obtained a pig of limbless phenotype. Mutations specific to this handicapped pig were identified using genome re-sequencing and comparative genomic analysis. We narrowed down the causal mutations to particular chromosomes and even several candidate genes and sites, such like a mutation-containing codon in gene BMP7 (bone morphogenetic protein) which was conserved in mammals but variable in lower vertebrates. Conclusions We parsed the limbless-related mutations in the light of evolution. The limbless pig shows phenocopy of the clades before legs were evolved. Our findings might help deduce the emergence of limbs during vertebrate evolution and should be appealing to the broad community of human genetics and evolutionary biology.

Induced Cardiomyocyte Proliferation: A Promising Approach to Cure Heart Failure

Unlike some lower vertebrates which can completely regenerate their heart, the human heart is a terminally differentiated organ. Cardiomyocytes lost during cardiac injury and heart failure cannot be replaced due to their limited proliferative capacity. Therefore, cardiac injury generally leads to progressive failure. Here, we summarize the latest progress in research on methods to induce cardiomyocyte cell cycle entry and heart repair through the alteration of cardiomyocyte plasticity, which is emerging as an effective strategy to compensate for the loss of functional cardiomyocytes and improve the impaired heart functions.