Biology subjects

Castro, A. F.

Publications and source records attributed to Castro, A. F..

4 recordsLinked to original sources

bioRxiv2025

Embryonic Spinocerebellar Ataxia Type 37 AUUUC Repeat RNA Causes Neurodevelopmental Defects in Zebrafish

Onset of many neurodegenerative and neuromuscular diseases usually starts in adulthood; however, recent advances point toward neurodevelopmental changes as drivers of late neurodegeneration. How early neuropathological features occur in these conditions remains unclear, which is critical for timely therapeutic intervention. Here, we provide evidence that neurodevelopmental axonal defects initiate a motor phenotype in a zebrafish model of spinocerebellar ataxia type 37 (SCA37), a degenerative hereditary condition caused by an ATTTC repeat in the DAB1 gene. We investigated neuronal defects triggered by the embryonic AUUUC repeat RNA and their effects later in life by transiently expressing this RNA in embryos and analyzing innervation and motor function. We found abnormalities in motor neuron axonal outgrowth and muscle innervation. We also discovered disrupted embryonic motor activity and reduced locomotor distance and velocity in late adult zebrafish, demonstrating motor impairment. Moreover, we showed that NOVA2 expression rescues axonal defects, indicating dysfunction of NOVA2-regulated neurodevelopmental processes. Overall, our results establish embryonic expression of the AUUUC repeat RNA as a driver of axonal and synaptic abnormalities, interfering with neuronal circuits and culminating in adult motor dysfunction.

neuroscience↗

bioRxiv2025

The Insertion of an ATTTC Repeat in an Alu Element Hyperactivates a Primate-Specific Neurodevelopmental Enhancer in Spinocerebellar Ataxia Type 37

Alu are evolutionarily very old primate-specific interspersed repeat elements that constitute [~]11% of the human genome. They are a source of short tandem repeats (STRs), which often expand in size and originate inherited neuromuscular and neurodegenerative disorders. How expanded STR insertion mutations within Alu STRs culminate in disease remains unknown. Here we report an Alu STR located in an intron of DAB1 that functions as a neurodevelopmental enhancer. We demonstrated that an ATTTC repeat insertion in this DAB1 Alu STR, known to cause spinocerebellar ataxia type 37 (SCA37), hyperactivates a neurodevelopmental DAB1 enhancer. Importantly, we showed that neurons derived from SCA37 subjects have higher levels of DAB1 expression and DAB1 overexpression causes abnormal axonal pathfinding in vivo. Overall, these results establish that neuronal dysregulation of a developmental DAB1 Alu STR enhancer contributes to SCA37 pathogenesis, an unexplored mechanism likely acting in many Alu STR diseases, potentially reshaping the therapeutic landscape.

genetics↗

bioRxiv2025

Quantifying neuronal differentiation using temporal topological persistence

Neuronal morphogenesis arises through coordinated neurite dynamics that generate cell-type specific dendritic branching during development. Recent advances in high-throughput time-lapse imaging techniques have transformed our ability to track such growth dynamics, yielding comprehensive anatomical datasets of neuronal morphologies. However, quantifying these structural trajectories during neuronal development remains a major challenge. We introduce the Temporal Topological Morphology Descriptor (TTMD), a framework that combines persistent topology with time-resolved neuronal imaging to quantify developmental trajectories of neuronal architecture. Applying TTMD to datasets of Drosophila sensory neurons, we show that developmental stages, branching processes, and mutant-specific growth dynamics can be decoded directly from topology without manual feature selection. Topological morphology descriptor (TMD) accurately resolve major developmental transitions in Class I Drosophila neurons, whereas temporal topology (TTMD) is required to uncover subtle alterations in branch dynamics caused by mutations in actin regulatory pathways in Class III Drosophila neurons. TTMD further enables automated topological tracking of branch emergence and retraction across development, overcoming the limitations of labor-intensive manual annotation. These results demonstrate that temporal topology provides a unified and interpretable language for neuronal morphogenesis, enabling the automated analysis of developmental neuroanatomy, and identifying pathological alterations in neuronal structure.

neuroscience↗

bioRxiv2020

The branching code: a model of actin-driven dendrite arborisation

Dendrites display a striking variety of neuronal type-specific morphologies, but the mechanisms and principles underlying such diversity remain elusive. A major player in defining the morphology of dendrites is the neuronal cytoskeleton, including evolutionarily conserved actin-modulatory proteins (AMPs). Still, we lack a clear understanding of how AMPs might support developmental phenomena such as neuron-type specific dendrite dynamics. To address precisely this level of in vivo specificity, we concentrated on a defined neuronal type, the class III dendritic arborisation (c3da) neuron of Drosophila larvae, displaying actin-enriched short terminal branchlets (STBs). Computational modelling reveals that the main branches of c3da neurons follow a general growth model based on optimal wiring, but the STBs do not. Instead, model STBs are defined by a short reach and a high affinity to grow towards the main branches. We thus concentrated on c3da STBs and developed new methods to quantitatively describe dendrite morphology and dynamics based on in vivo time-lapse imaging of mutants lacking individual AMPs. In this way, we extrapolated the role of these AMPs in defining STB properties. We propose that dendrite diversity is supported by the combination of a common step, refined by a neuron type-specific second level. For c3da neurons, we present a molecular model of how the combined action of multiple AMPs in vivo define the properties of these second level specialisations, the STBs. In briefA quantitative morphological dissection of the concerted actin-modulatory protein actions provides a model of dendrite branchlet outgrowth. HighlightsO_LIActin organisation in small terminal branchlets of Drosophila class III dendritic arborisation neurons C_LIO_LISix actin-modulatory proteins individually control the characteristic morphology and dynamics of branchlets C_LIO_LIQuantitative tools for dendrite morphology and branch dynamics enable a comparative analysis C_LIO_LIA two-step computational growth model reproduces c3da dendrite morphology C_LI

neuroscience↗