Biology subjects

Avetisyan, A.

Publications and source records attributed to Avetisyan, A..

5 recordsLinked to original sources

bioRxiv2026

Embryonic integrin signaling establishes a program of differential cell elongation in a growing proprioceptive organ

The ChO is a proprioceptive sensory organ that undergoes extensive morphological remodeling during larval growth. A key feature of this process is the dramatic elongation of cap cells, while adjacent ligament cells remain short. How these contrasting growth behaviors are established and coordinated is largely unknown. Using targeted RNAi screens of extracellular matrix (ECM) components, ECM receptors, and their intracellular effectors, we identified distinct molecular mechanisms controlling ChO architecture. We found that basement membrane components, including collagens and laminins, are required to maintain the characteristic straight morphology of cap cells, whereas Thrombospondin and Tiggrin contribute to the stability of cellular attachments. Unexpectedly, we discovered that Thrombospondin and an PS2{beta}PS integrin signaling module, comprising Talin and the ILK-PINCH-Parvin complex, regulate the relative lengths of cap and ligament cells. Cell-type-specific knockdown demonstrated that this pathway acts within ligament cells to restrict their elongation. Disruption of integrin signaling causes ligament cells to elongate dramatically at the expense of cap cell extension, effectively reversing their normal growth behaviors. Importantly, this function is distinct from the role of integrin-associated proteins in maintaining cellular attachments. Temporal manipulation of integrin expression revealed that the short morphology of ligament cells is established during a critical developmental time window during embryogenesis, before the organ becomes functional. Restoring integrin expression after hatching fails to rescue the phenotype, indicating that embryonic integrin signaling establishes a persistent developmental state. Together, these findings reveal that ligament cell elongation is actively restricted by an embryonically established integrin-dependent mechanism, providing the structural basis for subsequent cap cell elongation and organ maturation.

developmental biology↗

bioRxiv2025

A dNmnat-sensitized in vivo platform for unbiased discovery of regulators of neurodegeneration

Axon degeneration drives nervous system dysfunction in diverse neurological diseases and injuries. While key regulators of injury-induced Wallerian degeneration have been identified, approaches have largely relied on axotomy, a particularly extreme injury for a neuron. Here, we developed a forward genetic screening platform in the adult Drosophila wing that sensitizes neurons to degeneration through depletion of nicotinamide mononucleotide adenylyltransferase (dNmnat), the essential NAD+ biosynthetic enzyme. We screened 9,393 mutagenized chromosomes and recovered 59 mutations that suppress neurodegeneration induced by dNmant depletion, including the known pro-degenerative molecule dSarm, thereby validating our approach. We show loss of CG4098, the Drosophila homolog of the mammalian enzyme NUDT9, robustly preserved axons and induced widespread remodeling of NAD+-related metabolites, which provides a new link between cADP-ribose hydrolase activity and neuronal survival. We further show mutations in the transcription factor Abrupt resulted in elevated dNmnat protein levels and blocked axon degeneration, suggesting Abrupt normally tunes dNmnat levels and neuronal NAD+ homeostasis. dNmnat depletion is thus a versatile approach for unbiased discovery of axon death pathway components, each of which may provide new entry points for therapeutic strategies to preserve axons in neurodegenerative diseases.

neuroscience↗

bioRxiv2025

Hypoxia-inducible factor 1 protects neurons from Sarm1-mediated neurodegeneration

The Sarm1 NAD+ hydrolase drives neurodegeneration in many contexts, but how Sarm1 activity is regulated remains poorly defined. Using CRISPR/Cas9 screening, we found loss of VHL suppressed Sarm1-mediated cellular degeneration. VHL normally promotes O2-dependent constitutive ubiquitination and degradation of hypoxia-inducible factor 1 (HIF-1), but during hypoxia, HIF-1 is stabilized and regulates gene expression. We observed neuroprotection after depletion of VHL or other factors required for HIF-1 degradation, and expression of a non-ubiquitinated HIF-1 variant led to even stronger blockade of axon degeneration in mammals and Drosophila. Neuroprotection required HIF-1 DNA binding, prolonged expression, and resulted in broad gene expression changes. Unexpectedly, stabilized HIF-1 prevented the precipitous NAD+ loss driven by Sarm1 activation in neurons, despite NAD+ hydrolase activity being intrinsic to the Sarm1 TIR domain. Our work argues hypoxia inhibits Sarm1 activity through HIF-1 driven transcriptional changes, rendering neurons less sensitive to Sarm1-mediated neurodegeneration when in a hypoxic state. Competing interestsMarc Freeman is co-founder of Nura Bio, a biotech startup pursuing novel neuroprotective therapies including SARM1 inhibition. The remaining authors declare no competing interests.

neuroscience↗

bioRxiv2024

Drosophila with-no-lysine and frayed Act in Parallel to dSarm to Drive Neurodegeneration Following dNmnat Depletion

How neurons to sense when they are terminally dysfunctional and activate neurodegeneration remains poorly defined. The pro-degenerative NAD+ hydrolase dSarm/SARM1 can act as a metabolic sensor by detecting pathological changes in NAD+/NMN and subsequently induce catastrophic axon degeneration. Here we show Drosophila with-no-lysine kinase (dWnk), which can directly sense Cl-, K+ and osmotic pressure, is required for neurodegeneration induced by depletion of the NAD+ biosynthetic enzyme dNmnat. dWnk functions in parallel to dSarm and acts through the downstream kinase Frayed to promote axon degeneration and neuronal cell death. dWnk and dSarm ultimately converge on the BTB-Back domain molecule Axundead (Axed) to execute neurodegeneration. Our work argues that neurons use direct sensors of both metabolism (dSarm/SARM1) and ionic/osmotic status (dWnk) to evaluate cellular health and, when dysfunctional, promote neurodegeneration though a common axon death signaling molecule, Axundead.

neuroscience↗

bioRxiv2021

delilah, prospero and D-Pax2 constitute a gene regulatory network essential for the development of functional proprioceptors

Coordinated animal locomotion depends on the development of functional proprioceptors. While early cell-fate determination processes are well characterized, little is known about the terminal differentiation of cells within the proprioceptive lineage and the genetic networks that control them. In this work we describe a gene regulatory network consisting of three transcription factors-Prospero (Pros), D-Pax2 and Delilah (Dei)-that dictates two alternative differentiation programs within the proprioceptive lineage in Drosophila. We show that D-Pax2 and Pros control the differentiation of cap versus scolopale cells in the chordotonal organ lineage by, respectively, activating and repressing the transcription of dei. Normally, D-Pax2 activates the expression of dei in the cap cell but is unable to do so in the scolopale cell where Pros is co-expressed. We further show that D-Pax2 and Pros exert their effects on dei transcription via a 262 bp chordotonal-specific enhancer in which two D-Pax2- and three Pros-binding sites were identified experimentally. When this enhancer was removed from the fly genome, the cap- and ligament-specific expression of dei was lost, resulting in loss of chordotonal organ functionality and defective larval locomotion. Thus, coordinated larval locomotion depends on the activity of a dei enhancer that integrates both activating and repressive inputs for the generation of a functional proprioceptive organ.

developmental biology↗