Biology subjects

Grimes, D. T.

Publications and source records attributed to Grimes, D. T..

7 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

Active and Passive Mechanical Deficits Precede Spinal Curvature in a Zebrafish Model of Idiopathic Scoliosis

Idiopathic scoliosis is a common spinal disorder characterized by progressive three-dimensional curvature of unknown cause. Although biomechanical imbalance has long been proposed to contribute to scoliosis, the early physiological states that precede curvature onset remain poorly understood. Here, we investigated this problem using zebrafish uts2r3 mutants, which develop fully penetrant juvenile-onset spinal curvature following disruption of urotensin signaling. Transcriptomic analysis before curvature revealed altered expression of muscle-associated genes, suggesting that Uts2r3 influences axial muscle development or function. However, immunofluorescence, birefringence imaging, and quantitative analysis of myotome morphology showed that mutants lack overt muscle architectural defects or dystrophic pathology. By contrast, direct measurements of isolated larval trunks revealed pre-curvature biomechanical abnormalities: namely, uts2r3 mutants generated reduced active force following electrical stimulation while also exhibiting increased passive resistance to stretch. These findings identify urotensin signaling as a regulator of axial tissue biomechanics during growth and suggest that scoliosis-like curvature can arise from an early imbalance between active force generation and passive tissue stiffness. SignificanceSpinal curvature is common, but the biological events that cause the spine to bend during growth remain poorly understood. Animal models, especially zebrafish, make it possible to study these events before curvature begins. Zebrafish lacking urotensin signaling develop spinal curves that arise during juvenile growth, similar to idiopathic scoliosis in humans. Here, we demonstrate that zebrafish lacking the urotensin pathway receptor Uts2r3 develop an abnormal biomechanical state prior to curve onset. Their axial tissues generate less active force when contracting and, at the same time, show increased passive resistance to stretch--an unexpected combination that reveals a distinct pre-curvature biomechanical state. These findings suggest that spinal curvature can arise from an early imbalance in tissue mechanics during growth and identify urotensin signaling as a pathway that helps preserve spinal morphology through a biomechanical mechanism.

developmental biology↗

bioRxiv2025

Motile cilia spin the Reissner fiber, a tensioned and anchored extracellular thread essential for body morphogenesis

The Reissner fiber (RF) is an extracellular thread composed of the glycoprotein SCO-spondin (Sspo) that forms within cerebrospinal fluid (CSF) in the brain ventricles and central canal (CC) of vertebrates. Its assembly depends on motile cilia, yet how cilia and CSF flow transform secreted Sspo into a fiber that spans the length of the body axis has remained unknown. Using live imaging in zebrafish, we show that globular Sspo is remodeled into thin fibrils that anchor to the floor plate (FP), elongate, and spin together into a tensioned, posteriorly translocating RF. Fiber assembly draws on a shared CSF pool of Sspo but requires local ciliary activity for globule-to-fibril remodeling. Once assembled, the RF is anchored by dynamic fibrils that stabilize the fiber and preserve its tension. Perturbations that locally disrupt ciliary motility and RF integrity along the CC result in region-specific defects in axial morphogenesis. These findings identify the RF as a flow-responsive extracellular system that converts ciliary beating into mechanical structure, linking fluid dynamics to the large-scale shaping of the vertebrate body. HighlightsO_LIMotile cilia remodel Sspo globules into FP-anchored fibrils that bundle into RF. C_LIO_LIRF assembly draws on a shared CSF Sspo pool but requires local cilia activity. C_LIO_LILaser ablation reveals patterned RF tension constrained by dynamic FP anchors. C_LIO_LIRegional cilia defects cause local RF loss and corresponding body shape defects. C_LI

developmental biology↗

bioRxiv2025

Microtubule acetylation by TAT1 is essential for touch sensation in zebrafish but dispensable for embryonic development

Acetylation of -tubulin at lysine 40 (-tubK40Ac) is a conserved post-translational modification that occurs on the microtubule lumenal surface, but its developmental functions remain poorly defined. In zebrafish, morpholino knockdown of -tubulin acetyltransferase 1 (TAT1), the enzyme responsible for depositing -tubK40Ac marks, has been reported to cause severe developmental defects, whereas genetic loss-of-function studies in mice found no overt role in development. Here, we generated TAT1 loss-of-function alleles in zebrafish and found that, in contrast to morphants, mutants are viable, fertile, and develop normally. TAT1 mutants lack detectable -tubK40Ac in all examined tissues, indicating that no other enzyme compensates for loss of TAT1. Both cilia and neurons normally display high levels of -tubK40Ac and despite the complete loss of this modification in TAT1 mutants, gross cilia structure and motility were preserved, and cilia-dependent developmental processes remained intact. However, TAT1 mutants did exhibit defects in touch responsiveness, something which could be rescued by wild-type but not catalytically inactive TAT1. These findings demonstrate that TAT1 is solely responsible for -tubK40Ac in zebrafish and that, while dispensable for embryonic development and ciliary function, this modification is required for normal somatosensory behavior.

developmental biology↗

bioRxiv2025

A Conserved Domain of Cfap298 Governs Left-Right Symmetry Breaking in Vertebrates

Cfap298 is a highly conserved gene required for ciliary motility and dynein arm assembly. It plays a known role in Left-Right (LR) patterning in zebrafish and is linked to human ciliopathies. Here we describe a new Cfap298 mutant allele, Cfap298{Delta}3aa, which selectively interferes with LR axis establishment in mice. Mutant embryos display a range of laterality defects including situs solitus, situs inversus, and situs ambiguous, as indicated by abnormal heart, lung, and stomach positioning. At embryonic day 8.5, mutant embryos display abnormal Nodal, Pitx2, and Lefty1 expression patterns in the lateral plate mesoderm and midline, consistent with an early disruption in LR symmetry breaking. In mice, LR asymmetry is established by leftward fluid flow in the node, generated by planar-polarized cilia. Although cfap298 mutations are reported to affect cell polarity, we did not observe changes in cilia position, length, or planar cell polarity protein localization within the node, suggesting that Cfap298{Delta}3aafunctions at the level of cilia motility. Consistently, motile cilia lining the trachea of Cfap298{Delta}3aa mutants fail to beat. Expression of the Cfap298{Delta}3aa variant in zebrafish fails to rescue the LR defects of cfap298 (kurly) loss-of-function mutants. These results confirm that Cfap298 functions in LR axis formation in mammals and uncover a novel region of CFAP298 protein with a conserved and essential role in cilia motility. Summary StatementA novel Cfap298 mutation disrupts left-right patterning in mice by impairing ciliary motility, revealing a conserved protein region essential for this function across species.

developmental biology↗

bioRxiv2022

Urotensin II-Related Peptides, Urp1 and Urp2, Control Zebrafish Spine Morphology

The spine provides structure and support to the body, yet how it develops its characteristic morphology as the organism grows is little understood. This is underscored by the commonality of conditions in which the spine curves abnormally such as scoliosis, kyphosis and lordosis. Understanding the origin of such spinal curves has been challenging in part due to the lack of appropriate animal models. Recently, zebrafish have emerged as promising tools with which to understand the origin of spinal curves. Using zebrafish, we demonstrate that the Urotensin II-related peptides (URPs), Urp1 and Urp2, are essential for maintaining spine morphology. Urp1 and Urp2 are 10-amino acid cyclic peptides expressed by neurons lining the central canal of the spinal cord. Upon combined genetic loss of Urp1 and Urp2, adolescent-onset planar curves manifested in the caudal region of the spine, akin to a lordosis-like condition. Highly similar curves were caused by mutation of Uts2r3, an URP receptor. Quantitative comparisons revealed that Urotensin-associated curves were distinct from other zebrafish spinal curve mutants that more closely reflected idiopathic scoliosis or kyphosis. Last, we found that the Reissner fiber, a proteinaceous thread that sits in the central canal and has been implicated in the control of spine morphology, breaks down prior to curve formation in an idiopathic scoliosis model but was unperturbed by loss of Uts2r3. This suggests a Reissner fiber-independent mechanism of curvature in Urotensin-deficient mutants. Overall, our results show that Urp1 and Urp2 control zebrafish spine morphology and establish new animal models of lordosis-like curves.

developmental biology↗

bioRxiv2019

ZIP-5/bZIP transcription factor regulation of folate metabolism is critical for aging axon regeneration

Aging is associated with reduced capacity for tissue repair, perhaps the most critical of which is a decline in the ability of aged neurons to recover after injury. Identifying factors that improve the regenerative ability of aging neurons is a prerequisite for therapy design and remains an enormous challenge, yet many of the genes that play a role in regeneration of youthful axons do not regulate axon regeneration in older animals2,9, highlighting the need to identify aging-specific regeneration mechanisms. Previously, we found that increased DAF-16/FOXO activity enhances the regenerative ability of mechanosensory axons in aged animals9. Here we show that DAF-16/FOXO mediates its pro-regenerative effects by upregulating folate metabolism genes via the ZIP-5 bZIP transcription factor. Remarkably, dietary folic acid supplementation improves the regeneration of aging C. elegans axons. Enzymes regulating folate metabolism are also up-regulated in regenerating zebrafish fins, and we show that dietary folic acid supplementation post-amputation enhances fin regrowth in aging zebrafish. Our results demonstrate that boosting folate metabolism is a conserved and non-invasive approach to increase the regenerative capacity of aging neurons and tissues. Given that lower folate status has been linked with reduced cognition in the elderly17, maintaining optimal folate metabolism may be a general strategy to achieve healthy brain aging.

neuroscience↗