Biology subjects

Segal, R. A.

Publications and source records attributed to Segal, R. A..

5 recordsLinked to original sources

bioRxiv2025

Profiling local translatomes and RNA binding proteins of somatosensory neuronsreveals specializations of individual axons

Neurons extend long axons that traverse distinct microenvironments, yet how these compartments acquire and maintain specialized molecular identities remains unclear. Here, we use spatial translatomics to define the local axonal translatomes of dorsal root ganglion (DRG) neurons that mediate somatosensation. Translating Ribosome Affinity Purification and RNA sequencing revealed thousands of mRNAs that are preferentially translated within the central axons, peripheral axons, or DRG soma, establishing compartment-specific translational programs. Many of these transcripts encode ion channels, neurotransmitter receptors, and structural proteins that confer distinct electrophysiological, synaptic, and regenerative properties to each axon. Cross-dataset integration with single-cell RNA-seq demonstrated that neuropathic injury elicits highly compartment-specific remodeling of these localized translational programs. We identify polarized RNA regulons coordinated by the RNA-binding proteins (RBPs) SFPQ and SRSF10, which preferentially bind and traffic mRNAs to the peripheral or central axon, respectively. These findings reveal a mechanistic framework in which RBP-guided RNA sorting and local translation establish and dynamically tune subcellular specialization in sensory neurons. HIGHLIGHTSO_LIDistinct mRNAs are translated in peripheral or central axons (painseq.shinyapps.io/CompartmentTRAP/). C_LIO_LIAxonal translatomes enable localized regulation of electrophysiology, neuronal plasticity, and regeneration. C_LIO_LIThe RBPs, SFPQ and SRSF10, enable mRNA sorting to peripheral and central axons respectively. C_LI

neuroscience↗

bioRxiv2024

Satellite glial contact enhances differentiation and maturation of human induced sensory neurons

Sensory neurons generated from induced pluripotent stem cells (iSNs) are used to model human peripheral neuropathies, however current differentiation protocols produce sensory neurons with an embryonic phenotype. Peripheral glial cells contact sensory neurons early in development and contribute to formation of the canonical pseudounipolar morphology, but these signals are not encompassed in current iSN differentiation protocols. Here, we show that terminal differentiation of iSNs in co-culture with rodent Dorsal Root Ganglion satellite glia (rSG) advances their differentiation and maturation. Co-cultured iSNs develop a pseudounipolar morphology through contact with rSGs. This transition depends on semaphorin-plexin guidance cues and on glial gap junction signaling. In addition to morphological changes, iSNs terminally differentiated in co-culture exhibit enhanced spontaneous action potential firing, more mature gene expression, and increased susceptibility to paclitaxel induced axonal degeneration. Thus, iSNs differentiated in coculture with rSGs provide a better model for investigating human peripheral neuropathies.

neuroscience↗

bioRxiv2020

Diversity of developing peripheral glia revealed by single cell RNA sequencing

The peripheral nervous system responds to a wide variety of sensory stimuli, a process that requires great neuronal diversity. These diverse peripheral sensory neurons are closely associated with glial cells that originate from the neural crest (NC). However, the molecular nature and origins of diversity among peripheral glia is not understood. Here we used single cell RNA sequencing to profile and compare developing and mature glia from somatosensory lumbar dorsal root ganglia (DRG) and auditory spiral ganglia (SG). We found that the glial precursors (GPs) differ in their transcriptional profile and prevalence in these two systems. Despite their unique features, somatosensory and auditory GPs undergo convergent differentiation to generate myelinating and non-myelinating Schwann cells that are molecularly uniform. By contrast, although satellite glia surround the neuronal cell bodies in both ganglia, we found that those in the SG express multiple myelination-associated genes, while DRG satellite cells express components that suppress myelination. Lastly, we identified a set of glial signature genes that are also expressed by placode-derived supporting cells, providing new insights into commonalities among glia across the nervous system. This comprehensive survey of gene expression in peripheral glia constitutes a valuable resource for understanding how glia acquire specialized functions and how their roles differ across sensory modalities.

neuroscience↗

bioRxiv2020

Fast transport of RNA granules by direct interactions with KIF5A/KLC1 motors prevents axon degeneration

Complex neural circuitry requires stable connections formed by lengthy axons. To maintain these functional circuits, fast transport delivers RNAs to distal axons where they undergo local translation. However, the mechanism that enables long distance transport of non-membrane enclosed organelles such as RNA granules is not known. Here we demonstrate that a complex containing RNA and the RNA-binding protein (RBP) SFPQ interacts directly with a tetrameric kinesin containing the adaptor KLC1 and the motor KIF5A. We show that binding of SFPQ to KIF5A/KLC1 motor complex is required for axon survival and is impacted by KIF5A mutations that cause Charcot-Marie-Tooth (CMT) Disease. Moreover, therapeutic approaches that bypass the need for local translation of SFPQ-bound proteins prevent axon degeneration in CMT models. Collectively, these observations show that non-membrane enclosed organelles can move autonomously and that replacing axonally translated proteins provides a therapeutic approach to axonal degenerative disorders.

cell biology↗

bioRxiv2019

The Eya1 phosphatase mediates Shh-driven symmetric cell division of cerebellar granule cell precursors

During neural development, stem and precursor cells can divide either symmetrically or asymmetrically. The transition between symmetric and asymmetric cell divisions is a major determinant of precursor cell expansion and neural differentiation, but the underlying mechanisms that regulate this transition are not well understood. Here, we identify the Sonic hedgehog (Shh) pathway as a critical determinant regulating the mode of division of cerebellar granule cell precursors (GCPs). Using partial gain and loss of function mutations within the Shh pathway, we show that pathway activation determines spindle orientation of GCPs, and that mitotic spindle orientation directly correlates with the mode of division. Mechanistically, we show that the phosphatase Eya1 is essential for implementing Shh-dependent GCP spindle orientation. We identify atypical protein kinase C (aPKC) as a direct target of Eya1 activity and show that Eya1 dephosphorylates Threonine (T410) in the activation loop of this polarity complex component. Thus, Eya1 inactivates the cell polarity complex, resulting in reduced phosphorylation of Numb and other components that regulate the mode of division. This Eya1-dependent cascade is critical in linking spindle orientation, cell cycle exit and terminal differentiation. Together these findings demonstrate that a Shh-Eya1 regulatory axis selectively promotes symmetric cell divisions during cerebellar development by coordinating spindle orientation and cell fate determinants.\n\nSummary statementBiological responses to Shh signaling are specified by the magnitude of pathway activation and the cellular context. This study shows that potent Shh signaling regulates mitotic orientation and symmetric division of cerebellar granule cell precursors in a process that requires the phosphatase Eya1 and unequal distribution of cell fate determinants to daughter cells.

neuroscience↗