In vertebrates, the thymus is maximally active during the early life, when it coordinates the T cell developmental proceedings with the environmental cues to generate a pool of T cells responsible for life-long immunity. Apart from cytokines and growth factors, hormones play a pivotal role in bridging the thymic microenvironment with the external and internal macroenvironment of the host during the early life. The post-embryonic life in lower vertebrates (like fish and amphibians) involves a period of radical physiological remodeling, known as metamorphosis. Two endocrine axes: the thyroid hormones and the corticosteroids, cardinally regulate most of the physico-chemical changes during metamorphosis in these organisms. Functional execution of these signaling axes enables continuous integration of macro- and microenvironmental signals with the core genetic circuitry of development during the window of metamorphosis. As part of the coping strategies against the holistic eco-physiological changes during metamorphosis, the immune system, including the thymus, undergoes drastic changes in structure and function. However, there is a dearth of consolidated perspectives regarding the influence of these hormones on the metamorphosis-associated remodeling of the thymus and thymopoiesis, limiting our understanding of the most primitive and rudimentary forms of endocrine regulation over post-embryonic and perinatal thymopoiesis in vertebrates. This review chronicles the influence of these hormones on thymus formation, remodeling and thymopoiesis during metamorphosis in fish and amphibians, and traces their evolutionary conservation in higher vertebrates, which undergo direct, continuous development instead of metamorphosis. Insights emerging from this review might be pivotal for the conceptualization of the primitive forms of endocrine regulation over the thymus and thymopoiesis. Furthermore, the concepts might yield important clues about the evolutionary tuning of the growth-degeneration-regeneration cycle of the thymus as well as thymus-dependent immunity to endocrine pulsations during the early life in vertebrates.
Fetal alcohol spectrum disorders (FASD) encompass a broad range of effects caused by prenatal alcohol exposure. In the United States, conservative estimates place the incidence of FASD at a rate of 5 in 100 births. Children with FASD can have morphological afflictions including congenital defects of the brain, spinal cord, heart, eyes, and skeleton, as well as poor formation of facial structures such as the nose and mouth. Cognitive and behavioral abnormalities such as learning disabilities, socio-developmental delays and emotional disorders are also highly prevalent. There is no known cure for FASD and in utero detection methods are not available. In terms of urinary tract defects, kidney and renal related maladies may represent underreported aspects of FASD. To better understand the renal phenotypes associated with prenatal alcohol exposure, we employed the zebrafish, Danio rerio, a vertebrate species well suited for developmental nephrology and teratological work that has been used extensively to model FASD. We treated zebrafish embryos with ethanol then examined pattern formation and physiological activity of nephrons, which are the basic structural and functional unit of the kidney. Using whole mount in situ hybridization, we found that the formation of several cell types in the nephron blood filter and tubule, as well as renal progenitor populations, were perturbed by alcohol exposure. Interestingly, supplementation with all-trans retinoic acid, a vitamin A derivative associated with mitigating the effects of ethanol exposure in zebrafish and other animals, was sufficient to completely or partially rescue multiple ethanol induced kidney cell defects and restore nephron physiological activity. These studies have revealed several consequences of ethanol exposure that lead to the deregulation of renal ontogeny, and implicate a key role for reduced RA levels, thereby contributing useful insights relevant to the broader field of FASD research.
Mechanosensing and mechanotransduction are essential for all living cells. In mammals, PIEZO1 and PIEZO2 are two mechanically activated cation channels that serve as mechanosensors for a variety of physiological and pathological processes, ranging from touch sensing to sickle cell disease. These two channels are well evolutionarily conserved, and orthologous genes can be traced back to the origin of vertebrates, which underwent whole-genome duplications (WGDs). The number of paralogous genes originating from the vertebrate WGD varies across gene families. Thus, whether there are more PIEZO paralogous genes in vertebrates remains understudied. Here, we identified piezo3, a new paralog of the piezo gene family, and analyzed its evolutionary history using phylogenetic and syntenic analyses. The piezo3 gene is present in most vertebrate lineages but absent in birds and most mammals, likely due to nonfunctionalization after WGDs. In addition, we showed that this channel could mediate calcium flux in response to mechanical stimuli in HEK293T cells, suggesting that zebrafish Piezo3 exhibits PIEZO1/2-like activation and conduction channel functions. Our CRISPR mutation analysis revealed that the zebrafish piezo3 gene is not developmentally essential for skeletons and survival, possibly because its expression overlaps with other Piezo channels. Mutant zebrafish showed elevated sensitivity to mechanical force and increased locomotor activity under light illumination. Our results suggest that this new Piezo channel is widespread in vertebrates and may be critical for vertebrate adaptation by modulating mechanical sensing and light responses during evolution.
