Hox gene and development of the auditory circuit

Sound vibration is sensed by hair cells in the inner ear. The information is transmitted to the cochlear nucleus in the brainstem via spiral ganglion neurons. The information is further transmitted to higher relaying centers in the brain such as superior olivary complex and inferior colliculus. The connectivity between these components is topographically organized in a frequency-specific manner. It is known that the organization is well-established from the beginning of the circuit development. However, little is still known about the molecular mechanisms underlying the development of connectivity in the auditory circuit. Homeobox transcription factors of the Hox gene family are known for their involvement in early anterior-posterior axis patterning of neuronal progenitors in the hindbrain. Recent evidence indicates that they also play important roles in late aspects of neuronal development and establishment of topographic circuitry. Moreover, a mutation in the HOXA2 gene has been recently shown to be responsible for hearing deficits in humans. By means of spatiotemporally controlled Hoxa2 and Hoxb2 conditional mutations in the mouse we analyzed the involvement of these factors in auditory circuit development and connectivity

Distinct roles of Hoxa2 and Krox20 in the development of rhythmic neural networks controlling inspiratory depth, respiratory frequency, and jaw opening

<p>Abstract</p> <p>Background</p> <p>Little is known about the involvement of molecular determinants of segmental patterning of rhombomeres (r) in the development of rhythmic neural networks in the mouse hindbrain. Here, we compare the phenotypes of mice carrying targeted inactivations of <it>Hoxa2</it>, the only <it>Hox </it>gene expressed up to r2, and of <it>Krox20</it>, expressed in r3 and r5. We investigated the impact of such mutations on the neural circuits controlling jaw opening and breathing in newborn mice, compatible with Hoxa2-dependent trigeminal defects and direct regulation of <it>Hoxa2 </it>by Krox20 in r3.</p> <p>Results</p> <p>We found that <it>Hoxa2 </it>mutants displayed an impaired oro-buccal reflex, similarly to <it>Krox20 </it>mutants. In contrast, while <it>Krox20 </it>is required for the development of the rhythm-promoting parafacial respiratory group (pFRG) modulating respiratory frequency,<it> Hoxa2 </it>inactivation did not affect neonatal breathing frequency. Instead, we found that <it>Hoxa2</it>^-/-but not <it>Krox20</it>^-/-mutation leads to the elimination of a transient control of the inspiratory amplitude normally occurring during the first hours following birth. Tracing of r2-specific progenies of <it>Hoxa2 </it>expressing cells indicated that the control of inspiratory activity resides in rostral pontine areas and required an intact r2-derived territory.</p> <p>Conclusion</p> <p>Thus, inspiratory shaping and respiratory frequency are under the control of distinct <it>Hox</it>-dependent segmental cues in the mammalian brain. Moreover, these data point to the importance of rhombomere-specific genetic control in the development of modular neural networks in the mammalian hindbrain.</p

Opposing roles for Hoxa2 and Hoxb2 in hindbrain oligodendrocyte patterning

Oligodendrocytes are the myelin-forming cells of the vertebrate CNS. Little is known about the molecular control of region-specific oligodendrocyte development. Here, we show that oligodendrogenesis in the mouse rostral hindbrain, which is organized in a metameric series of rhombomere-derived (rd) territories, follows a rhombomere-specific pattern, with extensive production of oligodendrocytes in the pontine territory (r4d) and delayed and reduced oligodendrocyte production in the prepontine region (r2d, r3d). We demonstrate that segmental organization of oligodendrocytes is controlled by Hoxgenes, namely Hoxa2 and Hoxb2. Specifically, Hoxa2 loss of function induced a dorsoventral enlargement of the Olig2/Nkx2.2-expressing oligodendrocyte progenitor domain, whereas conditional Hoxa2 overexpression in the Olig2(+) domain inhibited oligodendrogenesis throughout the brain. In contrast, Hoxb2 deletion resulted in a reduction of the pontine oligodendrogenic domain. Compound Hoxa2(-/-)/Hoxb2(-/-) mutant mice displayed the phenotype of Hoxb2(-/-) mutants in territories coexpressing Hoxa2 and Hoxb2 (rd3, rd4), indicating that Hoxb2 antagonizes Hoxa2 during rostral hindbrain oligodendrogenesis. This study provides the first in vivo evidence that Hox genes determine oligodendrocyte regional identity in the mammalian brain

The Naturally Processed CD95L Elicits a c-Yes/Calcium/PI3K-Driven Cell Migration Pathway

Patients affected by chronic inflammatory disorders display high amounts of soluble CD95L. This homotrimeric ligand arises from the cleavage by metalloproteases of its membrane-bound counterpart, a strong apoptotic inducer. In contrast, the naturally processed CD95L is viewed as an apoptotic antagonist competing with its membrane counterpart for binding to CD95. Recent reports pinpointed that activation of CD95 may attract myeloid and tumoral cells, which display resistance to the CD95-mediated apoptotic signal. However, all these studies were performed using chimeric CD95Ls (oligomerized forms), which behave as the membrane-bound ligand and not as the naturally processed CD95L. Herein, we examine the biological effects of the metalloprotease-cleaved CD95L on CD95-sensitive activated T-lymphocytes. We demonstrate that cleaved CD95L (cl-CD95L), found increased in sera of systemic lupus erythematosus (SLE) patients as compared to that of healthy individuals, promotes the formation of migrating pseudopods at the leading edge of which the death receptor CD95 is capped (confocal microscopy). Using different migration assays (wound healing/Boyden Chamber/endothelial transmigration), we uncover that cl-CD95L promotes cell migration through a c-yes/Ca2+/PI3K-driven signaling pathway, which relies on the formation of a CD95-containing complex designated the MISC for Motility-Inducing Signaling Complex. These findings revisit the role of the metalloprotease-cleaved CD95L and emphasize that the increase in cl-CD95L observed in patients affected by chronic inflammatory disorders may fuel the local or systemic tissue damage by promoting tissue-filtration of immune cells

Pathophysiological Roles of the TRPV4 Channel in the Heart

The transient receptor potential vanilloid 4 (TRPV4) channel is a non-selective cation channel that is mostly permeable to calcium (Ca2+), which participates in intracellular Ca2+ handling in cardiac cells. It is widely expressed through the body and is activated by a large spectrum of physicochemical stimuli, conferring it a role in a variety of sensorial and physiological functions. Within the cardiovascular system, TRPV4 expression is reported in cardiomyocytes, endothelial cells (ECs) and smooth muscle cells (SMCs), where it modulates mitochondrial activity, Ca2+ homeostasis, cardiomyocytes electrical activity and contractility, cardiac embryonic development and fibroblast proliferation, as well as vascular permeability, dilatation and constriction. On the other hand, TRPV4 channels participate in several cardiac pathological processes such as the development of cardiac fibrosis, hypertrophy, ischemia–reperfusion injuries, heart failure, myocardial infarction and arrhythmia. In this manuscript, we provide an overview of TRPV4 channel implications in cardiac physiology and discuss the potential of the TRPV4 channel as a therapeutic target against cardiovascular diseases

Crack Propagation Modeling in Silicon: A Comprehensive Thermomechanical Finite-Element Model Approach for Power Devices

International audienceWafer handling during the manufacturing process introduces microcracks and flaws at the wafer edge. This paper aims at determining whether an initial crack would be able to propagate through the silicon active region of power devices when it is subjected to high electrothermal loads during operating conditions or accelerated thermal cycling tests. Failure analysis performed on these power devices has revealed some typical propagation paths. The most critical crack propagation cases (or paths) were determined by finite-element model simulations. The energy release rate has been calculated for different crack lengths, locations, or thermal loads, and then compared with the silicon critical energy release rate. Hence, different critical crack lengths have been determined. The effect of dice design, temperature, or mechanical properties of the materials on crack thresholds has been also investigated

Mouse Hoxa2 mutations provide a model for microtia and auricle duplication.

External ear abnormalities are frequent in newborns ranging from microtia to partial auricle duplication. Little is known about the molecular mechanisms orchestrating external ear morphogenesis. In humans, HOXA2 partial loss of function induces a bilateral microtia associated with an abnormal shape of the auricle. In mice, Hoxa2 inactivation at early gestational stages results in external auditory canal (EAC) duplication and absence of the auricle, whereas its late inactivation results in a hypomorphic auricle, mimicking the human HOXA2 mutant condition. By genetic fate mapping we found that the mouse auricle (or pinna) derives from the Hoxa2-expressing neural crest-derived mesenchyme of the second pharyngeal arch, and not from a composite of first and second arch mesenchyme as previously proposed based on morphological observation of human embryos. Moreover, the mouse EAC is entirely lined by Hoxa2-negative first arch mesenchyme and does not develop at the first pharyngeal cleft, as previously assumed. Conditional ectopic Hoxa2 expression in first arch neural crest is sufficient to induce a complete duplication of the pinna and a loss of the EAC, suggesting transformation of the first arch neural crest-derived mesenchyme lining the EAC into an ectopic pinna. Hoxa2 partly controls the morphogenesis of the pinna through the BMP signalling pathway and expression of Eya1, which in humans is involved in branchio-oto-renal syndrome. Thus, Hoxa2 loss- and gain-of-function approaches in mice provide a suitable model to investigate the molecular aetiology of microtia and auricle duplication.</jats:p

Spatial Abilities and Endodontic Access Cavity Preparation: Implications for Dental Education

Introduction: Access cavity preparation is a crucial step in root canal treatment but is one of the most complex procedures in the curriculum to learn, with students often reporting spatial orientation difficulties during drilling. The present study aimed to evaluate the influence of spatial abilities on the preparation of endodontic access cavities among third-year dental students. Materials and Methods: Students from Lyon dental faculty participated voluntarily. The mental rotation test (MRT) evaluated spatial ability. Students prepared access cavities on 3D-printed mandibular molars, subsequently scanned and assessed against eight evaluation points, including morphology, canal access, floor preservation and convergence angle. Principal component analysis (PCA) assessed dataset variations. Results: A total of 43 volunteers participated. PCA revealed two principal components accounting for 80.8% of variations: the first PC primarily consisted of MRT score (64.3%) and morphology (14.1%); the second comprised operative time (46.1%) and morphology (18.0%). There were significant differences in morphology based on MRT scores, but no correlation was found between other parameters. Discussion: Lower MRT scores were associated with larger cavity preparations, raising questions about potential curriculum adaptations to enhance spatial reasoning. The operative time was not correlated with higher MRT scores but did contribute to variations in cavity morphology. Conclusion: Spatial abilities have a substantial impact on the quality of endodontic access cavity preparations; further studies should evaluate if the incorporation of 3D atlas exercises could be beneficial