Local tissue mechanics control cardiac pacemaker cell embryonic patterning.

Cardiac pacemaker cells (CPCs) initiate the electric impulses that drive the rhythmic beating of the heart. CPCs reside in a heterogeneous, ECM-rich microenvironment termed the sinoatrial node (SAN). Surprisingly, little is known regarding the biochemical composition or mechanical properties of the SAN, and how the unique structural characteristics present in this region of the heart influence CPC function remains poorly understood. Here, we have identified that SAN development involves the construction of a "soft" macromolecular ECM that specifically encapsulates CPCs. In addition, we demonstrate that subjecting embryonic CPCs to substrate stiffnesses higher than those measured in vivo results in loss of coherent electrical oscillation and dysregulation of the HCN4 and NCX1 ion channels required for CPC automaticity. Collectively, these data indicate that local mechanics play a critical role in maintaining the embryonic CPC function while also quantitatively defining the range of material properties that are optimal for embryonic CPC maturation.

Assembly of the Cardiac Pacemaking Complex: Electrogenic Principles of Sinoatrial Node Morphogenesis.

Cardiac pacemaker cells located in the sinoatrial node initiate the electrical impulses that drive rhythmic contraction of the heart. The sinoatrial node accounts for only a small proportion of the total mass of the heart yet must produce a stimulus of sufficient strength to stimulate the entire volume of downstream cardiac tissue. This requires balancing a delicate set of electrical interactions both within the sinoatrial node and with the downstream working myocardium. Understanding the fundamental features of these interactions is critical for defining vulnerabilities that arise in human arrhythmic disease and may provide insight towards the design and implementation of the next generation of potential cellular-based cardiac therapeutics. Here, we discuss physiological conditions that influence electrical impulse generation and propagation in the sinoatrial node and describe developmental events that construct the tissue-level architecture that appears necessary for sinoatrial node function.

Trans-ovo permethrin exposure affects growth, brain morphology and cardiac development in quail.

Permethrin is a commonly used, highly effective pesticide in poultry agriculture, and has recently been trialed in conservation efforts to protect Galápagos finch hatchlings from an invasive ectoparasite. Although permethrin is considered safe for adults, pesticides can have health consequences when animals are exposed during early life stages. The few studies that have examined permethrin's effects in embryonic chicks and rats have shown hydrocephaly, anencephaly, reduced cellular energy conversion, and disruption of developing heart muscle. To test whether trans-ovo exposure of permethrin affects early development in birds, we exposed Japanese quail (Coturnix japonica) eggs to cotton treated with 1% permethrin that was incorporated into nests in two amounts (0.2, 0.8 g), each with a paired untreated cotton control group. When measured on incubation Day 15, we found permethrin-treated developing birds were smaller and showed signs of microcephaly, although mortality rates were the same. Despite no difference in heart mass, ventricular tissue was less compact, cardiac arteries were reduced and heart rates were slower in permethrin-treated birds. Differences in heart development were also observed at 5 days of incubation, indicating that abnormalities are present from early in cardiac development. Future studies are needed to examine permethrin's effects on developmental pathways and to determine if these effects persist after hatching to affect offspring health. This study provides evidence that permethrin can cross the eggshell to cause non-lethal but adverse effects on embryonic development, and studies should look beyond hatching when monitoring the efficacy of permethrin on wild bird populations.

Endocrine Regulation of Epimorphic Regeneration.

Studies aiming to uncover primary mechanisms of regeneration have predominantly focused on genetic pathways regulating specific stages in the regeneration process: wound healing, blastema formation, and pattern formation. However, studies across organisms show that environmental conditions and the physiological state of the animal can affect the rate or quality of regeneration, and endocrine signals are likely the mediators of these effects. Endocrine signals acting directly on receptors expressed in the tissue or via neuroendocrine pathways can affect regeneration by regulating the immune response to injury, allocation of energetic resources, or by enhancing or inhibiting proliferation and differentiation pathways involved in regeneration. This review discusses the cumulative knowledge in the literature about endocrine regulation of regeneration and its importance in future research to advance biomedical research.

Endocrine regulation of regeneration: Linking global signals to local processes.

Regeneration in amphibians and reptiles has been explored since the early 18th century, giving us a working in vivo model to study epimorphic regeneration in vertebrates. Studies aiming to uncover primary mechanisms of regeneration have predominantly focused on genetic pathways regulating specific stages of the regeneration process: wound healing, blastema formation and growth, and pattern formation. However, studies across organisms show that environmental conditions and physiological state of the animal can affect the rate or quality of regeneration, and endocrine signals are likely the mediators of these effects. Endocrine signals working/acting directly on receptors expressed in the structure or via neuroendocrine pathways can affect regeneration by modulating immune response to injury, allocation of energetic resources, or by enhancing or inhibiting proliferation and differentiation pathways in regenerating tissue. This review discusses the cumulative knowledge known about endocrine regulation of regeneration and important future research directions of interest to both ecological and biomedical research.

Restricted expression of karyopherin alpha mRNA in the sea urchin suggests a role in neurogenesis.

Karyopherin alpha (KAP-α) proteins are critical for the transport of many molecules into the nucleus. In this study, we identified three members of the KAP-α family in the sea urchin Lytechinus variegatus and described the developmental expression of these proteins. Although many importins are assumed to have ubiquitous expression, we found that all three genes were differentially expressed. Both LvKPNA1/5/6 and LvKPNA3/4 accumulated at high levels during cleavage, exhibiting cyclic expression as cells divided. By the blastula and gastrula stages expression decreased, remaining highest in the vegetal plate and archenteron, and by the prism/pluteus stages expression was restricted to the oral surface and gut. Expression of a third KAP-α gene, LvKPNA2/7, was examined in embryos from the mesenchyme blastula to pluteus stages. LvKPNA2/7 mRNA is present in vegetal cells of the mesenchyme blastula and, during gastrulation, it is localized to the archenteron and appears in additional groups of ectodermal cells. Prism/pluteus stage embryos expressed LvKPNA2/7 in the gut and scattered distribution of transcripts in the ciliary band resembled expression patterns of neural cells. We hypothesize that LvKPNA2/7 maintains pluripotency in the neural precursors prior to activation of neural differentiation and believe that this study is an important first step in an effort to better understand the roles of importins during embryogenesis.

Comparative endocrinology of leptin: assessing function in a phylogenetic context.

As we approach the end of two decades of leptin research, the comparative biology of leptin is just beginning. We now have several leptin orthologs described from nearly every major clade among vertebrates, and are moving beyond gene descriptions to functional studies. Even at this early stage, it is clear that non-mammals display clear functional similarities and differences with their better-studied mammalian counterparts. This review assesses what we know about leptin function in mammals and non-mammals, and gives examples of how these data can inform leptin biology in humans.