Atoh8 in development and disease

Atoh8 belongs to a large superfamily of transcriptional regulators called basic helix-loop-helix (bHLH) proteins. bHLH proteins have been identified in a wide range of organisms from yeast to humans. The members of this special group of transcription factors were found to be involved not only in embryonic development but also in disease initiation and its progression. Given their importance in several fundamental processes, the translation, subcellular location and turnover of bHLH proteins is tightly regulated. Alterations in the expression of bHLH proteins have been associated with multiple diseases also in context with Atoh8 which seems to unfold its functions as both transcriptional activator and repressor. Like many other bHLH transcription factors, so far, Atoh8 has also been observed to be involved in both embryonic development and carcinogenesis where it mainly acts as tumor suppressor. This review summarizes our current understanding of Atoh8 structure, function and regulation and its complex and partially controversial involvement in development and disease

atoh8\it atoh8 expression pattern in early zebrafish embryonic development

Atonal homologue 8 $\it (atoh8)$ is a basic helix-loop-helix transcription factor expressed in a variety of embryonic tissues. While several studies have implicated $\it atoh8$ in various developmental pathways in other species, its role in zebrafish development remains uncertain. So far, no studies have dealt with an in-depth in situ analysis of the tissue distribution of $\it atoh8$ in embryonic zebrafish. We set out to pinpoint the exact location of $\it atoh8$ expression in a detailed spatio-temporal analysis in zebrafish during the first 24 h of development (hpf). To our surprise, we observed transcription from pre-segmentation stages in the paraxial mesoderm and during the segmentation stages in the somitic sclerotome and not—as previously reported—in the myotome. With progressing maturation of the somites, the restriction of $\it atoh8$ to the sclerotomal compartment became evident. Double in situ hybridisation with $\it atoh8$ and $\it myoD$ revealed that both genes are expressed in the somites at coinciding developmental stages; however, their domains do not spatially overlap. A second domain of $\it atoh8$ expression emerged in the embryonic brain in the developing cerebellum and hindbrain. Here, we observed a specific expression pattern which was again in contrast to the previously published suggestion of $\it atoh8$transcription in neural crest cells. Our findings point towards a possible role of $\it atoh8$ in sclerotome, cerebellum and hindbrain development. More importantly, the results of this expression analysis provide new insights into early sclerotome development in zebrafish—a field of research in developmental biology which has not received much attention so far

Chicken embryo as a model in second heart field development

Previously, a single source of $\underline {progenitor}$ $\underline {cells}$ was thought to be responsible for the formation of the $\underline {cardiac}$ $\underline {muscle}$. However, the second heart field has recently been identified as an additional source of myocardial p$\underline {progenitor}$ $\underline {cells}$. The chicken embryo, which develops in the egg, outside the mother can easily be manipulated $\textit {in vivo}$ and $\textit {in vitro}$. Hence, it was an excellent model for establishing the concept of the second heart field. Here, our review will focus on the chicken model, specifically its role in understanding the second heart field. In addition to discussing historical aspects, we provide an overview of recent findings that have helped to define the chicken second heart field $\underline {progenitor}$ $\underline {cells}$. A better understanding of the second heart field development will provide important insights into the $\underline {congenital}$ $\underline {malformations}$ affecting $\underline {cardiac}$ $\underline {muscle}$ formation and function

The CXCR4/SDF-1 axis in the development of facial expression and non-somitic neck muscles

Trunk and head muscles originate from distinct embryonic regions: while the trunk muscles derive from the paraxial mesoderm that becomes segmented into somites, the majority of head muscles develops from the unsegmented cranial paraxial mesoderm. Differences in the molecular control of trunk versus head and neck muscles have been discovered about 25 years ago; interestingly, differences in satellite cell subpopulations were also described more recently. Specifically, the satellite cells of the facial expression muscles share properties with heart muscle. In adult vertebrates, neck muscles span the transition zone between head and trunk. Mastication and facial expression muscles derive from the mesodermal progenitor cells that are located in the first and second branchial arches, respectively. The cucullaris muscle (non-somitic neck muscle) originates from the posterior-most branchial arches. Like other subclasses within the chemokines and chemokine receptors, CXCR4 and SDF-1 play essential roles in the migration of cells within a number of various tissues during development. CXCR4 as receptor together with its ligand SDF-1 have mainly been described to regulate the migration of the trunk muscle progenitor cells. This review first underlines our recent understanding of the development of the facial expression (second arch-derived) muscles, focusing on new insights into the migration event and how this embryonic process is different from the development of mastication (first arch-derived) muscles. Other muscles associated with the head, such as non-somitic neck muscles derived from muscle progenitor cells located in the posterior branchial arches, are also in the focus of this review. Implications on human muscle dystrophies affecting the muscles of face and neck are also discussed

Local glucocorticoid administration impairs embryonic wound healing

Understanding the complex processes of fetal wound healing and skin regeneration can help to improve fetal surgery. As part of the integumentary system, the skin protects the newborn organism against environmental factors and serves various functions. Glucocorticoids can enter the fetal circulatory system by either elevated maternal stress perception or through therapeutic administration and are known to affect adult skin composition and wound regeneration. In the present study, we aimed at investigating the effects of local glucocorticoid administration on the process of embryonic wound healing. We performed in-ovo bead implantation of dexamethasone beads into skin incisional wounds of avian embryos and observed the local effects of the glucocorticoid on the process of skin regeneration through histology, immunohistochemistry and in-situ hybridization, using vimentin, fibronectin, E-cadherin, Dermo-1 and phospho-Histone H3 as investigational markers. Local glucocorticoid administration decelerated the healing of the skin incisional wounds by impairing mesenchymal contraction and re-epithelialization resulting in morphological changes, such as increased epithelialization and disorganized matrix formation. The results contribute to a better understanding of scarless embryonic wound healing and how glucocorticoids might interfere with the underlying molecular processes, possibly indicating that glucocorticoid therapies in prenatal clinical practice should be carefully evaluated

Murine transcription factor Math6 is a regulator of placenta development

The murine basic helix-loop-helix transcription (bHLH) factor mouse atonal homolog 6 (Math6) is expressed in numerous organs and supposed to be involved in several developmental processes. However, so far neither all aspects nor the molecular mechanisms of Math6 function have been explored exhaustively. To analyze the in vivo function of Math6 in detail, we generated a constitutive knockout (KO) mouse ($\it {Math6}$$^{−}/^{−}$) and performed an initial histological and molecular biological investigation of its main phenotype. Pregnant $\it {Math6}$$^{−}/^{−}$ females suffer from a disturbed early placental development leading to the death of the majority of embryos independent of the embryonic $\it {Math6}$ genotype. A few placentas and fetuses survive the severe uterine hemorrhagic events at late mid-gestation (E13.5) and subsequently develop regularly. However, these fetuses could not be born due to obstructions within the gravid uterus, which hinder the birth process. Characterization of the endogenous spatiotemporal $\it {Math6}$ expression during placenta development reveals that Math6 is essential for an ordered decidualization and an important regulator of the maternal-fetal endocrine crosstalk regulating endometrial trophoblast invasion and differentiation. The strongly disturbed vascularization observed in the maternal placenta appears as an additional consequence of the altered endocrine status and as the main cause for the general hemorrhagic crisis

In vivo drug testing during embryonic wound healing

The relevance of identifying pathological processes in the context of embryonic development is increasingly gaining attention in terms of professionalized prenatal care. To analyze local effects of prenatally administered drugs during embryonic development, the model organism of the chicken embryo can be used in a first exploratory approach. For the examination of local dexamethasone administration — as an exemplary drug — common bead implantation protocols have been adapted to serve as an in vivo technique for local drug testing during embryonic skin regeneration. For this, acrylic beads were soaked in a dexamethasone solution and implanted into skin incisional wounds of 4-day-old chicken embryos. After further incubation, the effects of the applied substance on the process of embryonic skin regeneration were analyzed using histological and molecular biological techniques. This data descriptor contains a detailed microsurgical protocol, a representative video demonstration, and exemplary results of local glucocorticoid-induced changes during embryonic wound healing. To conclude, this method allows for the analysis of the local effects of a particular substance on a cellular level and can be extended to serve as an in vivo technique for numerous other drugs to be tested on embryonic tissue

CXCR4/SDF1 signalling promotes sensory neuron clustering in vitro\textit {in vitro}

During the development of the peripheral nervous system, a subgroup of neural crest cells migrate away from the neural tube and coalesce into clusters of sensory neurons (ganglia). Mechanisms involved in the formation of the dorsal root ganglia (DRG) from neural crest cells are currently unclear. Mice carrying mutations in $\textit {Cxcr4}$, which is known to control neural crest migration, exhibit malformed DRG. In order to investigate this phenomenon, we modelled sensory neuron differentiation $\textit {in vitro}$ by directing the differentiation of human induced pluripotent stem cells into sensory neurons under SDF1 (agonist), AMD3100 (antagonist) or control conditions. There we could show a marked effect on the clustering activity of the neurons $\textit {in vitro}$, suggesting that $\textit {CXCR4}$ signalling is involved in facilitating DRG condensation

New insights into the diversity of branchiomeric muscle development

Branchiomeric skeletal muscles are a subset of head muscles originating from skeletal muscle progenitor cells in the mesodermal core of pharyngeal arches. These muscles are involved in facial expression, mastication, and function of the larynx and pharynx. Branchiomeric muscles have been the focus of many studies over the years due to their distinct developmental programs and common origin with the heart muscle. A prerequisite for investigating these muscles’ properties and therapeutic potential is understanding their genetic program and differentiation. In contrast to our understanding of how branchiomeric muscles are formed, less is known about their differentiation. This review focuses on the differentiation of branchiomeric muscles in mouse embryos. Furthermore, the relationship between branchiomeric muscle progenitor and neural crest cells in the pharyngeal arches of chicken embryos is also discussed. Additionally, we summarize recent studies into the genetic networks that distinguish between first arch-derived muscles and other pharyngeal arch muscles

Dynamically changing mental stress parameters of first-year medical students over the three-year course of the COVID-19 pandemic

Numerous research results have already pointed towards the negative influence of increased mental stress on educational processes and motivational criteria. It has also been shown that the global public health crisis induced by COVID-19 was related to anxiety symptoms and elevated levels of distress. To holistically elucidate the dynamics of the pandemic-related mental stress of first-year medical students, the associated parameters of three different cohorts were measured at the beginning of the pandemic-related restrictions on university life in Germany (20/21), at the peak of the COVID-19-related restrictions (21/22) and during the easing of the restrictions in the winter term 22/23. In a repeated cross-sectional study design, the constructs of worries, tension, demands and joy were collected from first-year medical students ($\it n$ = 578) using the Perceived Stress Questionnaire. The results demonstrate significantly increased values of the constructs worries ($\it p$ < 0.001), tension ($\it p$ < 0.001) and demands ($\it p$ < 0.001) at the peak of the pandemic related restrictions compared to the previous and following year as well as significantly decreasing values of general joy of life during the observed period of 3 years (all $\it p$-values < 0.001). A confirmatory factor analysis was performed to verify the questionnaire's factor structure regarding the addressed target group during the pandemic (CFI: 0.908, RMSEA: 0.071, SRMR: 0.052). These data, collected over a period of three years, provide information regarding dynamically manifesting mental stress during the COVID-19 pandemic, and refer to new areas of responsibility for the faculties to adequately counteract future crisis situations