Biology subjects

Eisen, J. S.

Publications and source records attributed to Eisen, J. S..

6 recordsLinked to original sources

bioRxiv2026

Serotonergic Control of Spine Morphology During Growth in Zebrafish

Scoliosis is a three-dimensional deformity of the vertebral column that commonly emerges during growth, yet the biological mechanisms that initiate and drive curve progression remain poorly understood. Serotonin (5-hydroxytryptamine [5-HT]) has long been linked to scoliosis through its relationship with pineal melatonin signaling and through genetic associations with human disease, but its role in spinal morphogenesis has remained unclear. Here, using zebrafish, we show that serotonergic signaling is required for normal spine morphology. Transient exposure to 5-HT during development induces later spinal abnormalities, while loss of Tph2, the principal enzyme required for neuronal 5-HT synthesis, causes progressive three-dimensional spinal curvature during juvenile growth, mimicking aspects of adolescent idiopathic scoliosis (AIS). tph2 mutants undergo initially normal vertebral patterning while targeted ablation of the pineal gland does not induce scoliosis, arguing against a pineal or early skeletal origin for the 5-HT-associated spinal curves. The Reissner fiber, which has been linked to spinal curvature in zebrafish, also formed normally in tph2 mutants. Instead, mutants showed a marked reduction in Fev-expressing intraspinal serotonergic neurons together with increased locomotor activity. Mutants exhibited longer swim bouts and shorter periods of inactivity between bouts. Importantly, these motor defects were evident shortly before the onset of overt spinal curvature. Together, these findings identify neuronal serotonin as a critical regulator of spinal stability and support a model in which altered serotonergic control of motor function changes the mechanical environment experienced by the growing spine, increasing its susceptibility to progressive curvature.

developmental biology↗

bioRxiv2026

Social modulation of activity and orientation fosters complex interactions in young zebrafish

Zebrafish are an important model organism for investigating collective behavior and neuropsychiatric disorders due to attributes such as fast development, high genetic homology with humans and a rich behavioral repertoire. Social behavior in zebrafish emerges as early as twelve days post-fertilization, building toward diverse, coordinated, and complex adult interactions. Most studies on social phenotypes, including in zebrafish, have focused on adult animals and assess isolated traits such as aggression, boldness, or social memory, leaving the critical period of early development when sociality emerges and the mechanisms underlying social behavior establishment largely unexplored. We present here a behavior analysis pipeline that identifies features describing general locomotion and social behavior based on simple geometric criteria. We apply this analysis to pairs of freely interacting two-week-old zebrafish and characterize nascent social preference. We find that young zebrafish favor a specific range of inter-fish distances, creating a social space characterized by specific modulation of locomotion features. Through quantitative analysis and modeling, we show that this proximity behavior is largely established through a turning bias toward counterparts and a socially induced suppression of the variance in turning angles over broader ranges of inter-fish distances. Furthermore, we describe how proximity fosters engagement by young zebrafish in transient, complex short-range physical interactions that include various forms of inter-fish contacts, reminiscent of patterns described in adult animals. Our approach has broad applications for understanding the ontogeny of sociality and collective behaviors and describing subtle phenotypes associated with various human disorders.

animal behavior and cognition↗

bioRxiv2023

Gap junction mediated bioelectric coordination is required for slow muscle development, organization, and function

Bioelectrical signaling, intercellular communication facilitated by membrane potential and electrochemical coupling, is emerging as a key regulator of animal development. Gap junction (GJ) channels can mediate bioelectric signaling by creating a fast, direct pathway between cells for the movement of ions and other small molecules. In vertebrates, GJ channels are formed by a highly conserved transmembrane protein family called the Connexins. The connexin gene family is large and complex, presenting a challenge in identifying the specific Connexins that create channels within developing and mature tissues. Using the embryonic zebrafish neuromuscular system as a model, we identify a connexin conserved across vertebrate lineages, gjd4, which encodes the Cx46.8 protein, that mediates bioelectric signaling required for appropriate slow muscle development and function. Through a combination of mutant analysis and in vivo imaging we show that gjd4/Cx46.8 creates GJ channels specifically in developing slow muscle cells. Using genetics, pharmacology, and calcium imaging we find that spinal cord generated neural activity is transmitted to developing slow muscle cells and synchronized activity spreads via gjd4/Cx46.8 GJ channels. Finally, we show that bioelectrical signal propagation within the developing neuromuscular system is required for appropriate myofiber organization, and that disruption leads to defects in behavior. Our work reveals the molecular basis for GJ communication among developing muscle cells and reveals how perturbations to bioelectric signaling in the neuromuscular system may contribute to developmental myopathies. Moreover, this work underscores a critical motif of signal propagation between organ systems and highlights the pivotal role played by GJ communication in coordinating bioelectric signaling during development.

developmental biology↗

bioRxiv2021

Enteric nervous system modulation of luminal pH modifies the microbial environment to promote intestinal health

The enteric nervous system (ENS) controls many aspects of intestinal homeostasis, including parameters that shape the habitat of microbial residents. Previously we showed that zebrafish lacking an ENS, due to deficiency of the sox10 gene, develop intestinal inflammation and bacterial dysbiosis, with an expansion of proinflammatory Vibrio strains. To understand the primary defects resulting in dysbiosis in sox10 mutants, we investigated how the ENS shapes the intestinal environment in the absence of microbiota and associated inflammatory responses. We found that intestinal transit, intestinal permeability, and luminal pH regulation are all aberrant in sox10 mutants, independent of microbially induced inflammation. Treatment with the proton pump inhibitor, omeprazole, corrected the more acidic luminal pH of sox10 mutants to wild type levels. Omeprazole treatment also prevented overabundance of Vibrio and ameliorated inflammation in sox10 mutant intestines. Treatment with the carbonic anhydrase inhibitor, acetazolamide, caused wild type luminal pH to become more acidic, and increased both Vibrio abundance and intestinal inflammation. We conclude that a primary function of the ENS is to regulate luminal pH, which plays a critical role in shaping the resident microbial community and regulating intestinal inflammation. Author SummaryThe intestinal microbiota is an important determinant of health and disease and is shaped by the environment of the gut lumen. The nervous system of the intestine, the enteric nervous system (ENS), helps maintain many aspects of intestinal health including a healthy microbiota. We used zebrafish with a genetic mutation that impedes ENS formation to investigate how the ENS prevents pathogenic shifts in the microbiota. We found that mutants lacking an ENS have a lower luminal pH, higher load of pathogenic bacteria, and intestinal inflammation. We showed that correcting the low pH, using the commonly prescribed pharmacological agent omeprazole, restored the microbiota and prevented intestinal inflammation. Conversely, we found that lowering the luminal pH of wild type animals, using the drug acetazolamide, caused expansion of pathogenic bacteria and increased intestinal inflammation. From these experiments, we conclude that a primary function of the ENS is to maintain normal luminal pH, thereby constraining intestinal microbiota community composition and promoting intestinal health.

microbiology↗

bioRxiv2018

Epigenetic factors coordinate intestinal development

Intestinal epithelium development depends on epigenetic modifications, but whether that is also the case for other intestinal tract cell types remains unclear. We found that functional loss of a DNA methylation machinery component, ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1), leads to reduced enteric neuron number, changes in neuronal morphology, and severe intestinal smooth muscle disruption. Genetic chimeras revealed that Uhrf1 functions both cell-autonomously in enteric neuron progenitors and cell-non-autonomously in surrounding intestinal cells. Uhrf1 recruits the DNA methyltransferase Dnmt1 to unmethylated DNA during replication. Dnmt1 is also expressed in enteric neuron and smooth muscle progenitors. dnmt1 mutants show a strong reduction in enteric neuron number and disrupted intestinal smooth muscle. Because dnmt1;uhrf1 double mutants have a similar phenotype to dnmt1 and uhrf1 single mutants, Dnmt1 and Uhrf1 must function together during enteric neuron and intestinal muscle development. This work shows that genes controlling epigenetic modifications are important in coordinating intestinal tract development, provides the first demonstration that these genes are important in ENS development, and advances uhrf1 and dnmt1 as potential new Hirschsprung disease candidates.\n\nSummaryThis work provides evidence that DNA methylation factors are important in all cell types that contribute to development of a functional intestine.

developmental biology↗

bioRxiv2017

Image velocimetry and spectral analysis enable quantitative characterization of larval zebrafish gut motility

Summary StatementWe present a new image analysis technique using image velocimetry and spectral analysis that returns quantitative measures of gut contraction strength, frequency, and wave speed that can be used to study gut motility and other cellular movements.\n\nAbstractNormal gut function requires rhythmic and coordinated movements that are affected by developmental processes, physical and chemical stimuli, and many debilitating diseases. The imaging and characterization of gut motility, especially regarding periodic, propagative contractions driving material transport, are therefore critical goals. Whereas previous image analysis approaches have successfully extracted properties related to temporal frequency of motility modes, robust measures of contraction magnitude remain elusive. We developed a new image analysis method based on image velocimetry and spectral analysis that reveals temporal characteristics such as frequency and wave propagation speed, while also providing quantitative measures of the amplitude of gut motions. We validate this approach using several challenges to larval zebrafish, imaged with differential interference contrast microscopy. Both acetylcholine exposure and feeding increase frequency and amplitude of motility. Larvae lacking enteric nervous system gut innervation show the same average motility frequency, but reduced and less variable amplitude compared to wild-types. Our image analysis approach enables insights into gut dynamics in a wide variety of developmental and physiological contexts and can also be extended to analyze other types of cell movements.

developmental biology↗