19 research outputs found
Molecular basis of gap junctional communication in the CNS of the leech Hirudo medicinalis
Gap junctions are intercellular channels that allow the passage of ions and small molecules between cells. In the nervous system, gap junctions mediate electrical coupling between neurons. Despite sharing a common topology and similar physiology, two unrelated gap junction protein families exist in the animal kingdom. Vertebrate gap junctions are formed by members of the connexin family, whereas invertebrate gap junctions are composed of innexin proteins. Here we report the cloning of two innexins from the leech Hirudo medicinalis. These innexins show a differential expression in the leech CNS: Hm-inx1 is expressed by every neuron in the CNS but not in glia, whereas Hm-inx2 is expressed in glia but not neurons. Heterologous expression in the paired Xenopus oocyte system demonstrated that both innexins are able to form functional homotypic gap junctions. Hm-inx1 forms channels that are not strongly gated. In contrast, Hm-inx2 forms channels that are highly voltage-dependent; these channels demonstrate properties resembling those of a double rectifier. In addition, Hm-inx1 and Hm-inx2 are able to cooperate to form heterotypic gap junctions in Xenopus oocytes. The behavior of these channels is primarily that predicted from the properties of the constituent hemichannels but also demonstrates evidence of an interaction between the two. This work represents the first demonstration of a functional gap junction protein from a Lophotrochozoan animal and supports the hypothesis that connexin-based communication is restricted to the deuterostome clade
Exosomes in Cardiovascular Medicine
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Brn3a regulates neuronal subtype specification in the trigeminal ganglion by promoting Runx expression during sensory differentiation
The transcription factor Brn3a, product of the pou4f1 gene, is expressed in most sensory neurons throughout embryogenesis. Prior work has demonstrated a role for Brn3a in the repression of early neurogenic genes; here we describe a second major role for Brn3a in the specification of sensory subtypes in the trigeminal ganglion (TG). Sensory neurons initially co-express multiple Trk-family neurotrophin receptors, but are later marked by the unique expression of TrkA, TrkB or TrkC. Maturation of these sensory subtypes is known to depend on the expression of Runx transcription factors. Newborn Brn3a knockout mice fail to express TrkC, which is associated in the TG with mechanoreceptors, plus a set of functional genes associated with nociceptor subtypes. In embryonic Brn3a-/- ganglia, the normal expression of Runx3 is never initiated in TrkC+ neurons, and Runx1 expression is greatly attenuated in TrkA+ nociceptors. These changes are accompanied by expanded expression of TrkB in neurons that abnormally express multiple Trks, followed by the loss of TrkC and TrkA expression. In transgenic embryos expressing a Brn3a-VP16 dominant transactivator, Runx3 mRNA expression is increased, suggesting that it is a direct regulatory target of Brn3a. Chromatin immunoprecipitation confirms that Brn3a binds in vivo to a conserved upstream enhancer element within histone H3-acetylated chromatin in the Runx3 locus. Together these data show that Brn3a acts upstream of the Runx factors, which then repress TrkB expression to allow establishment of the non-overlapping Trk receptor profiles and correct terminally differentiated phenotypes
POU-domain factor Brn3a regulates both distinct and common programs of gene expression in the spinal and trigeminal sensory ganglia
BACKGROUND: General somatic sensation is conveyed to the central nervous system at cranial levels by the trigeminal ganglion (TG), and at spinal levels by the dorsal root ganglia (DRG). Although these ganglia have similar functions, they have distinct embryological origins, in that both contain neurons originating from the neural crest, while only the TG includes cells derived from the placodal ectoderm. RESULTS: Here we use microarray analysis of E13.5 embryos to demonstrate that the developing DRG and TG have very similar overall patterns of gene expression. In mice lacking the POU-domain transcription factor Brn3a, the DRG and TG exhibit many common changes in gene expression, but a subset of Brn3a target genes show increased expression only in the TG. In the wild-type TG these Brn3a-repressed genes are silent, yet their promoter regions exhibit histone H3-acetylation levels similar to constitutively transcribed gene loci. This increased H3-acetylation is not observed in the DRG, suggesting that chromatin modifications play a role in cell-specific target gene regulation by Brn3a. CONCLUSION: These results demonstrate that one developmental role of Brn3a is to repress potential differences in gene expression between sensory neurons generated at different axial levels, and to regulate a convergent program of developmental gene expression, in which functionally similar populations of neurons are generated from different embryological substrates
Transcriptional and Post-transcriptional Gene Regulation by Long Non-coding RNA.
Advances in genomics technology over recent years have led to the surprising discovery that the genome is far more pervasively transcribed than was previously appreciated. Much of the newly-discovered transcriptome appears to represent long non-coding RNA (lncRNA), a heterogeneous group of largely uncharacterised transcripts. Understanding the biological function of these molecules represents a major challenge and in this review we discuss some of the progress made to date. One major theme of lncRNA biology seems to be the existence of a network of interactions with microRNA (miRNA) pathways. lncRNA has been shown to act as both a source and an inhibitory regulator of miRNA. At the transcriptional level, a model is emerging whereby lncRNA bridges DNA and protein by binding to chromatin and serving as a scaffold for modifying protein complexes. Such a mechanism can bridge promoters to enhancers or enhancer-like non-coding genes by regulating chromatin looping, as well as conferring specificity on histone modifying complexes by directing them to specific loci
Exosomes in Cardiovascular Medicine
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<p>The full text of this article can
be found here<b>. </b><a href="https://link.springer.com/article/10.1007/s40119-017-0091-9">https://link.springer.com/article/10.1007/s40119-017-0091-9</a></p><p></p>
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as the articles they are being presented alongside. Moreover, all sponsorship
and disclosure information is included to provide complete transparency and
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Cloning and expression of a leech complexin
Release of neurotransmitter from presynaptic nerve terminals is mediated by SNARE proteins, which are located on the vesicle and plasma membranes. These proteins form a SNARE complex thought to mediate membrane fusion. Complexin is a soluble protein essential for transmitter release, which has been postulated to bind to and stabilise the SNARE complex. We have cloned a complexin homologue, Hm-cpx1, from the leech, Hirudo medicinalis. This protein is expressed in only a subset of neurons in the leech CNS, including the Retzius and P neurons. It is 33% identical to rat complexin I, and 44% identical to squid complexin. Sequence conservation is particularly high in the predicted SNARE binding domain
Molecular characterization and embryonic expression of innexins in the leech Hirudo medicinalis
Gap junctions are direct intercellular channels that permit the passage of ions and small signaling molecules. The temporal and spatial regulation of gap junctional communication is, thus, one mechanism by which cell interactions, and hence cell properties and cell fate, may be regulated during development. The nervous system of the leech, Hirudo medicinalis, is a particularly advantageous system in which to study developmental mechanisms involving gap junctions because interactions between identified cells may be studied in vivo in both the embryo and the adult. As in most invertebrates, gap junctions in the leech are composed of innexin proteins, which are distantly related to the vertebrate pannexins and are encoded by a multi-gene family. We have cloned ten novel leech innexins and describe the expression of these, plus two other previously reported members of this gene family, in the leech embryo between embryonic days 6 and 12, a period during which the main features of the central nervous system are established. Four innexins are expressed in neurons and two in glia, while several innexins are expressed in the excretory, circulatory, and reproductive organs. Of particular interest is Hm-inx6, whose expression appears to be restricted to the characterized S cell and two other neurons putatively identified as presynaptic to this cell. Two other innexins also show highly restricted expressions in neurons and may be developmentally regulated
The Functions of Long Non-Coding RNA during Embryonic Cardiovascular Development and Its Potential for Diagnosis and Treatment of Congenital Heart Disease
Congenital heart disease (CHD) arises due to errors during the embryonic development of the heart, a highly regulated process involving an interplay between cell-intrinsic transcription factor expression and intercellular signalling mediated by morphogens. Emerging evidence indicates that expression of these protein-coding genes is controlled by a plethora of previously unappreciated non-coding RNAs operating in complex feedback-control circuits. In this review, we consider the contribution of long non-coding RNA (lncRNA) to embryonic cardiovascular development before discussing applications to CHD diagnostics and therapeutics. We discuss the process of lineage restriction during cardiovascular progenitor cell differentiation, as well as the subsequent patterning of the cardiogenic progenitor fields, taking as an example the regulation of NODAL signalling in left-right patterning of the heart. lncRNA are a highly versatile group. Nuclear lncRNA can target specific genomic sequences and recruit chromatin remodelling complexes. Some nuclear lncRNA are transcribed from enhancers and regulate chromatin looping. Cytoplasmic lncRNA act as endogenous competitors for micro RNA, as well as binding and sequestering signalling proteins. We discuss features of lncRNA that limit their study by conventional methodology and suggest solutions to these problems