Biology subjects

Kocabas, A.

Publications and source records attributed to Kocabas, A..

5 recordsLinked to original sources

bioRxiv2025

Neuromodulation of Swarming Behavior in C. elegans: Insights into the Conserved role of Calsyntenins

Collective animal behaviors arise from a complex interplay between internal physiological states and external environmental cues. In Caenorhabditis elegans, favorable conditions promote dispersal, while stressors like food scarcity or overcrowding trigger aggregation. Here, we describe a distinct behavior termed as swarming, where C. elegans move and feed in aggregates despite abundant food availability. While environmental factors have been implicated in this behavior, the underlying genetic and molecular mechanisms remain unclear. We identify a novel role for the conserved calsyntenin protein CASY-1 in regulating swarming. Through genetic, behavioral, and optogenetic approaches, we show that CASY-1 functions in sensory neurons to modulate the neuropeptide pigment-dispersing factor (PDF) signaling. Mutants in casy-1 show impaired PDF-1 signaling and reduced inhibition of the serotonin pathway, a known regulator of social behaviors. This dysregulation, along with its associated mechanosensory and foraging defects, likely contributes to the swarming phenotype. Our findings reveal a putative neuromodulatory pathway critical for swarming behavior in C. elegans.

neuroscience↗

bioRxiv2025

Controlling the synchronization and symmetry breaking of coupled bacterial pili on active biofilm carpets

In the low Reynolds number regime, active biological systems utilize nonreciprocal cyclic activities to achieve motility, as seen in the spinning of bacterial flagella and the beating of cilia. Coupling among these active mechanical components leads to synchronization, and emergence of metachronal waves. Here, we report that biofilms of Pseudomonas nitroreducens form active carpet-like surfaces textured with diverse topological defects, generating Mexican-wave-like collective behavior in which bacteria periodically lift up. On these active surfaces, nonreciprocally coupled extension and retraction activities of bacterial pili drives these collective oscillations. Surprisingly, this collective behavior exhibits left-right asymmetry across the biofilm driving unidirectionally propagating waves. We discover that this directionality is primarily governed by an aging-related frequency gradient across the biofilm. Leveraging these insights, we further demonstrate the ability to control the collective dynamics of these waves, including symmetry breaking, transitions from spiral waves into target and propagating plane waves by manipulating the elastic properties of biofilms. Overall, our findings illuminate the fundamental role of nonreciprocally interacting active components in regulating synchronization, collective dynamics, and symmetry-breaking phenomena in biological systems.

biophysics↗

bioRxiv2021

Altered temporal sequence of transcriptional regulators in the generation of human cerebellar granule cells

Brain development is regulated by conserved transcriptional programs across species, but little is known about divergent mechanisms that create species-specific characteristics. Among brain regions, the cerebellum is now recognized to contribute to human cognitive evolution having a broad range of non-motor cognitive functions in addition to motor control. Emerging studies highlight the complexity of human cerebellar histogenesis, compared with non-human primates and rodents, making it important to develop methods to generate human cerebellar neurons that closely resemble those in the developing human cerebellum. Here we report a rapid and simple protocol for the directed derivation of the human ATOH1 lineage, the precursor of excitatory cerebellar neurons, from human pluripotent stem cells (hPSC), and strategies to decrease culture variability; a common limitation in hPSC studies. Upon transplantation into juvenile mice, early postmitotic hPSC-derived cerebellar granule cells migrated along glial fibers and integrated into the cerebellar cortex. By Translational Ribosome Affinity Purification (TRAP)-seq, the ATOH1 lineage most closely resembled human cerebellar tissue in the second trimester. Unexpectedly, TRAP-seq identified a heterochronic shift in the expression of RBFOX3 (NeuN) and NEUROD1, which are classically associated with differentiated neurons, within granule cell progenitors (GCPs) in the human external granule layer. This molecular divergence may provide the mechanism by which the GCP pool persists into year two post birth in humans, but only lasts for two weeks in mice. Our approach provides a scalable in vitro model of the human ATOH1 lineage that yields cerebellar granule cells within 48 days as well as a strategy for identifying uniquely human cellular and molecular characteristics.

developmental biology↗

bioRxiv2020

Distinct expression of select and transcriptome-wide isolated 3'UTRs suggests critical roles in development and transition states

Mature mRNA molecules are typically considered to be comprised of a 5UTR, a 3UTR and a coding region (CDS), all attached until degradation. Unexpectedly, however, there have been multiple recent reports of widespread differential expression of mRNA 3UTRs and their cognate coding regions, resulting in the expression of isolated 3UTRs (i3UTRs); these i3UTRs can be highly expressed, often in reciprocal patterns to their cognate CDS. Similar to the role of other lncRNAs, isolated 3UTRs are likely to play an important role in gene regulation but little is known about the contexts in which they are deployed. To begin to parse the functions of i3UTRs, here we carry out in vitro, in vivo and in silico analyses of differential 3UTR/CDS mRNA ratio usage across tissues, development and cell state changes both for a select list of developmentally important genes as well as through unbiased transcriptome-wide analyses. Across two developmental paradigms we find a distinct switch from high i3UTR expression of stem cell related genes in proliferating cells compared to newly differentiated cells. Our unbiased transcriptome analysis across multiple gene sets shows that regardless of tissue, genes with high 3UTR to CDS ratios belong predominantly to gene ontology categories related to cell-type specific functions while in contrast, the gene ontology categories of genes with low 3UTR to CDS ratios are similar and relate to common cellular functions. In addition to these specific findings our data provide critical information from which detailed hypotheses for individual i3UTRs can be tested-with a common theme that i3UTRs appear poised to regulate cell-specific gene expression and state. Significance StatementThe widespread existence and expression of mRNA 3 untranslated sequences in the absence of their cognate coding regions (called isolated 3UTRs or i3UTRs) opens up considerable avenues for gene regulation not previously envisioned. Each isolated 3UTR may still bind and interact with micro RNAs, RNA binding proteins as well as other nucleic acid sequences, all in the absence or low levels of cognate protein production. Here we document the expression, localization and regulation of i3UTRs both within particular biological systems as well as across the transcriptome. As this is an entirely new area of experimental investigation these early studies are seminal to this burgeoning field.

cell biology↗

bioRxiv2020

Novel genetic features of human and mouse Purkinje cell differentiation defined by comparative transcriptomics.

Comparative transcriptomics between differentiating human pluripotent stem cells (hPSC) and developing mouse neurons offers a powerful approach to compare genetic and epigenetic pathways in human and mouse neurons. To analyze human Purkinje cell (PC) differentiation, we optimized a protocol to generate hPSC-PCs that formed synapses when cultured with mouse cerebellar glia and granule cells and fired large calcium currents, measured with the genetically encoded calcium indicator jRGECO1a. To directly compare global gene expression of hPSC-PCs with developing mouse PCs, we used translating ribosomal affinity purification (TRAP). As a first step, we used Tg(Pcp2-L10a-Egfp) TRAP mice to profile actively transcribed genes in developing postnatal mouse PCs, and used metagene projection to identify the most salient patterns of PC gene expression over time. We then created a transgenic Pcp2-L10a-Egfp TRAP hESC line to profile gene expression in differentiating hPSC-PCs, finding that the key gene expression pathways of differentiated hPSC-PCs most closely matched those of late juvenile, mouse PCs (P21). Comparative bioinformatics identified classical PC gene signatures as well as novel mitochondrial and autophagy gene pathways during the differentiation of both mouse and human PCs. In addition, we identified genes expressed in hPSC-PCs but not mouse PCs and confirmed protein expression of a novel human PC gene, CD40LG, expressed in both hPSC-PCs and native human cerebellar tissue. This study therefore provides the first direct comparison of hPSC-PC and mouse PC gene expression and a robust method for generating differentiated hPSC-PCs with human-specific gene expression for modeling developmental and degenerative cerebellar disorders. Significance StatementTo compare global gene expression features of differentiating human pluripotent stem cell-derived Purkinje cells (hPSC-PC) and developing mouse Purkinje cells (PC) we derived hPSC-PCs and compared gene expression datasets from human and mouse PCs. We optimized a differentiation protocol that generated hPSC-PCs most similar in gene expression to mouse P21 PCs. Metagene projection analysis of mouse PC gene expression over postnatal development identified both classical PC marker genes as well as novel mitochondrial and autophagy gene pathways. These key gene expression patterns were conserved in differentiating hPSC-PCs. We further identified differences in timing and expression of key gene sets between mouse and hPSC-PCs and confirmed expression of a novel human PC marker, CD40LG, in human cerebellar tissue.

developmental biology↗