Biology subjects

Seidel, C. W.

Publications and source records attributed to Seidel, C. W..

7 recordsLinked to original sources

bioRxiv2026

A naturally evolved mutation in cavefish mc3r reshapes energy homeostasis across development in a nutrient-limited environment.

Food availability in natural habitats is often unpredictable and drives the selection of adaptive strategies in organisms to survive food scarcity. However, the genetic and molecular mechanisms that enable animals to survive under such nutritional extremes are poorly understood. Naturally adapted organisms therefore provide powerful genetic systems for uncovering the mechanisms that maintain energy homeostasis under nutritional extremes. Here, we leveraged the cavefish Astyanax mexicanus to identify a naturally occurring Thr166Met missense mutation in the melanocortin 3 receptor (mc3r) that reprograms energy homeostasis to facilitate adaptation to nutrient deprivation. To determine its functional consequences, we introduced the mutation into zebrafish mc3r using CRISPR/Cas9 genome editing. We show that adult mc3r mutants exhibit increased body size, adiposity, and hyperglycemia relative to wild-type animals, recapitulating key metabolic features of Tinaja cavefish and identifying mc3r as the first causal gene behind cavefish hyperglycemia. Investigations for early developmental consequences of the mutation revealed accelerated yolk utilization in mutant zebrafish larvae and strikingly elevated metabolic rates relative to WT, thus, uncovering a previously unrecognized role for mc3r in regulating energy expenditure. Importantly, the phenotype was also observed in Tinaja cavefish revealing a novel cavefish phenotype and establishing causal role for mc3r in elevated metabolic rate phenotype of cavefish. Together, these findings reveal that the Thr166Met variant produces distinct physiological consequences across life stages, enhanced energy storage and hyperglycemia in adulthood despite elevated larval energy expenditure. We propose that increased larval metabolism may support the energetic demands of enhanced foraging, whereas increased adiposity and blood glucose later in life provide energy reserves during periods of nutrient scarcity. More broadly, our study demonstrates how a single naturally evolved coding variant can reshape energy homeostasis across development and contribute to adaptation to nutrient-poor environments.

evolutionary biology↗

bioRxiv2026

Loss of polr1c disrupts myelination in a zebrafish model of POLR1C-associated disease

Pathogenic variants in POLR1C, which encodes a shared subunit of RNA Polymerases (Pols) I and III, cause Treacher Collins syndrome (TCS) and POLR3-related leukodystrophy. While Pol I and Tp53-dependent mechanisms have been implicated in the pathogenesis of TCS, the basis of hypomyelination in POLR1C-associated POLR3-related leukodystrophy remains incompletely understood. Here, we show that polr1c mutant zebrafish exhibit reduced myelination in addition to previously described craniofacial anomalies. Oligodendrocyte precursor cells exhibit increased activation of the Tp53 pathway; however, these cells do not undergo apoptosis. Consistent with this finding, tp53 inhibition reduces cell death in polr1c mutants but fails to restore myelination, indicating that myelination deficits are not driven by Tp53-dependent progenitor loss in this model. polr1c mutants also exhibit reduced rRNA transcription by Pol I and reduced expression of some Pol III-transcribed tRNAs. Altogether, these data indicate distinct tissue-specific responses to polr1c deficiency and suggest persistent impairment of rRNA transcription contributes to deficient myelin development. These findings expand the developmental consequences of polr1c loss and advance our understanding of the molecular basis of POLR1C-associated diseases.

developmental biology↗

bioRxiv2026

Morphological, molecular, and functional evidence for a CNS-like oral nerve ring in the sea anemone Nematostella vectensis

The emergence of centralized nervous systems reflects a major inflection point in evolution, enabling animals to integrate diverse inputs and coordinate complex behaviors. Neural centralization is typically associated with Bilateria, whereas their sister group, Cnidaria (jellyfish, anemones, and corals), has long been thought to rely on diffuse nerve nets mediating simple reflexes. This view, reinforced by limited anatomical and molecular data, has left unresolved whether cnidarians can form localized centers for neural processing, a question sharpened by the growing recognition of their diverse behavioral repertoires. Here we show that the sea anemone Nematostella vectensis possesses an oral nerve ring composed of ganglion-like condensations, a hallmark of centralized organization. These neurons are enriched for excitatory, inhibitory, and modulatory receptors but lack sensory or ciliary markers, yielding a molecular profile most consistent with bilaterian interneurons. Genetic disruption of a conserved inhibitory receptor subunit predominantly expressed in the oral nerve ring delayed the initiation of swallowing in a novel feeding paradigm, demonstrating a potential role in behavioral regulation. Together, these findings provide converging anatomical, molecular, and functional evidence that cnidarians can assemble localized integrative centers, suggesting that key elements of neural centralization predated the cnidarian-bilaterian split.

evolutionary biology↗

bioRxiv2025

Rdh10-mediated Retinoic Acid Signaling Regulates the Neural Crest Cell Microenvironment During ENS Formation

The enteric nervous system (ENS) is formed from vagal neural crest cells (NCC), which generate most of the neurons and glia that regulate gastrointestinal function. Defects in the migration or differentiation of NCC in the gut can result in gastrointestinal disorders such as Hirschsprung disease (HSCR). Although mutations in many genes have been associated with the etiology of HSCR, a significant proportion of affected individuals have an undetermined genetic diagnosis. Therefore, its important to identify new genes, modifiers and environmental factors that regulate ENS development and disease. Rdh10 catalyzes the first oxidative step in the metabolism of vitamin A to its active metabolite, RA, and is therefore a central regulator of vitamin A metabolism and retinoic acid (RA) synthesis during embryogenesis. We discovered that retinol dehydrogenase 10 (Rdh10) loss-of-function mouse embryos exhibit intestinal aganglionosis, characteristic of HSCR. Vagal NCC form and migrate in Rdh10 mutant embryos but fail to invade the foregut. Rdh10 is highly expressed in the mesenchyme surrounding the entrance to the foregut and is essential between E7.5-E9.5 for NCC invasion into the gut. Comparative RNA-sequencing revealed downregulation of the Ret-Gdnf-Gfr1 gene signaling network in Rdh10 mutants, which is critical for vagal NCC chemotaxis. Furthermore, the composition of the extracellular matrix through which NCC migrate is also altered, in part by increased collagen deposition. Collectively this restricts NCC entry into the gut, demonstrating that Rdh10-mediated vitamin A metabolism and RA signaling pleiotropically regulates the NCC microenvironment during ENS formation and in the pathogenesis of intestinal aganglionosis.

developmental biology↗

bioRxiv2021

S. pombe wtf genes use dual transcriptional regulation and selective protein exclusion from spores to cause meiotic drive

Meiotic drivers bias gametogenesis to ensure their transmission into more than half the offspring of a heterozygote. In Schizosaccharomyces pombe, wtf meiotic drivers destroy the meiotic products (spores) that do not inherit the driver from a heterozygote, thereby reducing fertility. wtf drivers encode both a Wtfpoison protein and a Wtfantidote protein using alternative transcriptional start sites. Here, we analyze how the expression and localization of the Wtf proteins are regulated to achieve drive. We show that transcriptional timing and selective protein exclusion from developing spores ensure that all spores are exposed to Wtf4poison, but only the spores that inherit wtf4 receive a dose of Wtf4antidote sufficient for survival. In addition, we show that the Mei4 transcription factor, a master regulator of meiosis, controls the expression of the wtf4poison transcript. This dual transcriptional regulation, which includes the use of a critical meiotic transcription factor, likely complicates the universal suppression of wtf genes without concomitantly disrupting spore viability. We propose that these features contribute to the evolutionary success of the wtf drivers. Author SummaryKiller meiotic drivers are one type of selfish DNA sequence. When only one copy of a killer meiotic driver is found in a genome, the driver is expected to be transmitted to only half of the gametes (e.g. eggs or sperm). Killer meiotic drivers, however, kill developing gametes that do not inherit them, giving the driver a transmission advantage into the next generation. The molecular mechanisms used by these killers are not well understood. In this work, we analyzed how one killer meiotic driver, wtf4 from fission yeast, ensures targeted gamete (spore) killing. Previous work showed that wtf meiotic drivers encode a poison protein that is transmitted to all spores and an antidote protein that rescues only spores that inherit the locus. Here, we show that different timing of the expression of the two proteins, combined with differential inclusion of the proteins in developing spores, both contribute to targeted spore killing. We also demonstrate that wtf4 exploits an essential gene expression pathway, making it difficult for the genome to prevent this locus from being expressed and killing. This extends our knowledge both of how these genetic parasites act and how they are equipped to evade host suppression mechanisms.

genetics↗

bioRxiv2021

The feedback regulator Nord controls Dpp/BMP signaling via extracellular interaction with Dally in the Drosophila wing

The Drosophila BMP 2/4 homologue Decapentaplegic (Dpp) acts as a morphogen to regulate diverse developmental processes, including wing morphogenesis. Transcriptional feedback regulation of this pathway ensures tightly controlled signaling outputs to generate the precise pattern of the adult wing. Nevertheless, few direct Dpp target genes have been explored and our understanding of feedback regulation remains incomplete. Here, we employ transcriptional profiling following dpp conditional knockout to identify nord, a novel Dpp/BMP feedback regulator. Nord mutants generated by CRISPR/Cas9 mutagenesis produce a smaller wing and display low penetrance venation defects. At the molecular level, nord encodes a heparin-binding protein and we show that its overexpression is sufficient to antagonize Dpp/BMP signaling. Further, we demonstrate that Nord physically and genetically interacts with the Dpp/BMP co-receptor Dally. In sum we propose that Nord acts with Dally to fine tune Dpp/BMP signaling, with implications for both developmental and disease models. Impact statementFunctional analyses of the Drosophila homologue of Neuron Derived Neurotrophic Factor reveal a new mode of extracellular heparan sulfate proteoglycan regulation required for proper morphogen action.

developmental biology↗

bioRxiv2017

Cellular, ultrastructural and molecular analyses of epidermal cell development in the planarian Schmidtea mediterranea

The epidermis is essential for animal survival, providing both a protective barrier and cellular sensor to external environments. The generally conserved embryonic origin of the epidermis, but the broad morphological and functional diversity of this organ across animals is puzzling. We define the transcriptional regulators underlying epidermal lineage differentiation in the planarian Schmidtea mediterranea, an invertebrate organism that, unlike fruitflies and nematodes, continuously replaces its epidermal cells. We find that Smed-p53, Sox and Pax transcription factors are essential regulators of epidermal homeostasis, and act cooperatively to regulate genes associated with early epidermal precursor cell differentiation, including a tandemly arrayed novel gene family (prog) of secreted proteins. Additionally, we report on the discovery of distinct and previously undescribed secreted organelles whose production is dependent on the transcriptional activity of soxP-3, and which we term Hyman vesicles.

developmental biology↗