Biology subjects

Donati, A.

Publications and source records attributed to Donati, A..

8 recordsLinked to original sources

bioRxiv2026

Evolution and integration of a novel cell type in the housefly Love Spot

The addition of new neuron types is thought to underlie the evolution of complex nervous systems, yet the mechanisms by which they arise remain unclear. Here we investigate the evolution of a novel target detection photoreceptor in the housefly Musca domestica. In males, a dorso-frontal eye region known as the "Love Spot" enables rapid detection and tracking of females during mating flights. In this region, R7 photoreceptors - normally dedicated to color vision - are repurposed for target detection through altered Rhodopsin expression, physiology, and circuit connectivity. We show that these Love Spot R7 cells (LsR7) are initially specified as canonical R7 photoreceptors but later adopt a chimeric identity combining transcription factors normally associated with either color or motion vision. The sex-determination transcription factor Doublesex (Dsx) is strongly upregulated after R7 specification and, together with the transcription factor Spineless, drives the LsR7 gene regulatory program. Because Dsx upregulation occurs after initial axon targeting to the medulla, LsR7 axons subsequently shorten to connect with lamina neurons and OFF-pathway motion vision circuits. These findings show how new combinations of cell-identity regulators can generate novel neural cell types while revealing developmental constraints imposed by evolutionary history.

Developmental Biology↗

bioRxiv2025

Sensory receptor expansion and neural accommodation in butterfly color vision

The evolution of complex brains required existing neurons and neural circuits to accommodate new inputs. The genetic and developmental mechanisms that enable such integration are largely unknown. Butterflies evolved more complex retinal mosaics through the addition of a second R7 color photoreceptor per ommatidium (unit eye). In Drosophila, the unique R7 makes a stochastic choice to express one of two opsin genes. In butterflies, the two R7s make independent stochastic cell fate choices in each ommatidium, producing three ommatidial types instead of two. Here, we investigate the developmental basis of this change and how the butterfly brain accommodates expanded sensory receptor input. We first identified the changes in gene expression that cause a second R7 cell to be specified. We then modified Drosophila retinas to have butterfly-like transcription factor expression, causing recruitment of an additional R7. The two R7s make independent stochastic choices, like butterflies, leading to three stochastically distributed ommatidial types. In Drosophila, the two R7 subtypes connect to their target neurons, either yDm8 or pDm8. Dm8 neurons of both types are born in excess and Dm8s that do not find connections with their cognate y or pR7s undergo apoptosis. In the presence of extra R7s in butterfly-like fly retinas, additional Dm8s are retained, leading to two Dm8s per medulla column that make appropriate connections with the matching R7 subtypes, facilitating the expansion of color vision. We propose that the presence of cells that would otherwise die provide developmental flexibility that can allow brains to accommodate newly evolved inputs.

developmental biology↗

bioRxiv2025

Role of Hypertrophic Adipocytes, Collagen VI and CD38 in Fat Fibrosis of Patients with Obesity

Fat fibrosis correlates to metabolic consequences in patients with obesity, and is due to three types of collagen: I and III (fibrillar) and VI (non-fibrillar). In this sudy the extent of fibrosis in obese patients (n 50) was significant only in visceral parenchymal fat (4.7% vs 2.5% in controls (n 15) P<0.0001) and not in subcutaneous fat. Electron microscopy, in vivo and in vitro data, suggested that obese adipocytes are responsible for fibrillar collagen (I and III) production. COL6 (gene producing the non fibrillar form) resulted less expressed. In line, patients with COL6 mutations, showed increased fibrotic tissue even in subcutaneous fat: about 6.5 times vs controls in the patient with the severe form (Ullrich) and 2.8 times in two patients with the milder form (Bethlem). Approximately 15% of obese adipocytes were dead (perilipin1 negative), and consequent infiltrating macrophages showed hyperexpression of CD38, an ectoenzyme implicated in systemic fibrosis. Correlations with gene expression confirmed the importance also of myofibroblasts and the extracellular matrix peptidase D. All together our data support a role for obese adipocytes in the fibrillar collagen production and evidentiate collagen VI and CD38 as new molecular determinants, reinforcing the idea of a multi-factorial origin of fat fibrosis.

cell biology↗

bioRxiv2025

Potent neutralization of Marburg virus by a vaccine-elicited monoclonal antibody

Marburg virus (MARV) is a filovirus that causes a severe and often lethal hemorrhagic fever. Despite the increasing frequency of MARV outbreaks, no vaccines or therapeutics are licensed for use in humans. Here, we designed mutations that improve the expression and thermostability of the prefusion MARV glycoprotein (GP) ectodomain trimer, which is the sole target of neutralizing antibodies and vaccines in development. We discovered a fully human monoclonal antibody, MARV16, that broadly neutralizes all MARV isolates as well as Ravn virus and Dehong virus with 40 to 100-fold increased potency relative to previously described antibodies. We determined a cryo-electron microscopy structure of MARV16-bound MARV GP showing that MARV16 recognizes a prefusion-specific epitope spanning GP1 and GP2, blocking receptor binding and preventing conformational changes required for viral entry. We further reveal the architecture of the MARV GP glycan cap, which shields the receptor binding site (RBS), underscoring architectural similarities with distantly related filovirus GPs. MARV16 and previously identified RBS-directed antibodies can bind MARV GP simultaneously, paving the way for a MARV therapeutic antibody cocktail. MARV GP stabilization along with the discovery of a potent neutralizing antibody will advance treatment and prevention options for MARV.

immunology↗

bioRxiv2024

Early-life stress impairs development of functional interactions and neuronal activity within prefrontal-amygdala networks in vivo

Early-life stress (ELS), such as parental neglect or abuse, predisposes an individual to develop mental disorders. Disease hallmarks include heightened amygdala reactivity and impaired prefrontal cortex-amygdala functional interactions, already during childhood and adolescence. However, which cellular and circuit mechanisms underlie these hallmarks, as well as the altered developmental trajectory of prefrontal-amygdala networks, is poorly understood. Here we performed simultaneous in vivo local-field potential and multi-unit recordings under light urethane anaesthesia in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) of male and female pre-juvenile or adolescent mice, exposed to a resource scarcity model of ELS. We find a developmentally transient low-theta (3-5 Hz) oscillatory hypercoupling within mPFC-BLA networks in pre-juvenile ELS males which seems to result from a precocious development of coupling strength after ELS. In the mPFC, neuronal spiking activity was decreased in pre-juvenile males and the local theta entrainment of spike firing disrupted. In BLA, both sexes showed an increase in firing activity in a subpopulation of neurons after ELS, also confirmed by an increase in {Delta}FosB-positive neurons in BLA, which we identified to be non-GABAergic. Directed interactions, i.e. the ability to entrain spike firing in mPFC to the theta rhythm in BLA and vice versa, were also impaired predominantly in pre-juvenile males after ELS, while females showed a milder phenotype. These early sex-dependent impairments in the functional development of prefrontal-amygdala circuits may promote aberrant development of emotional behaviours after ELS and may predispose to a disease phenotype later on.

neuroscience↗

bioRxiv2024

Planar cell polarity coordination in a cnidarian embryo provides clues to animal body axis evolution

Body axis specification is a crucial event in animal embryogenesis and was an essential evolutionary innovation for founding the animal kingdom. It involves two distinct components that coordinate to establish the spatial organisation of the embryo: initiation of cascades of regionalised gene expression and orientation of morphogenetic processes such as body elongation. Intense interest in the first component has revealed Wnt/{beta}-catenin signalling as ancestrally responsible for initiating regional gene expression, but the evolutionary origin of oriented morphogenesis has received little attention. Here, by addressing the cell and morphological basis of body axis development in embryos of the cnidarian Clytia hemisphaerica, we have uncovered a simple and likely ancestral coordination mechanism between Wnt/{beta}-catenin signalling and directed morphogenesis. We show that the ligand Wnt3, known to initiate oral gene expression via localised Wnt/{beta}-catenin pathway activation, also has a key {beta}-catenin-independent role in globally orienting planar cell polarity (PCP) to direct morphogenesis along the oral-aboral axis. This PCP orientation occurs in two distinct steps: local orientation by Wnt3 and global propagation by conserved core PCP protein interactions along the body axis. From these findings we propose novel scenarios for PCP-driven symmetry-breaking underlying the emergence of the animal body plan.

developmental biology↗

bioRxiv2024

Spontaneous activity of striatal projection neurons supports maturation of striatal inputs to substantia nigra dopaminergic neurons

Spontaneous activity of neurons during early ontogenesis is instrumental for stabilization and refinement of developing neuronal connections. The role of spontaneous activity in synaptic development has been described in detail for cortical-like structures. Yet, very little is known about activity-dependent development of long-range inhibitory projections, such as projections from striatum. Here, we show that striatal projection neurons (SPNs) in dorsal striatum are spontaneously active in P4-P14 mice. Spontaneous activity was detected in both direct-pathway SPNs (dSPNs) and indirect-pathway SPNs (iSPNs). Most of the spontaneously active cells were in striosomes - a chemical compartment in striatum defined by expression of {micro}-opioid receptor. Higher excitability of both striosomal dSPNs and iSPNs was related to their intrinsic excitability properties (higher action potential half-width and IV slope). Tonic activation of muscarinic M1 receptor maintains the spontaneous activity of striosomal SPNs, the effect being stronger in iSPNs and weaker in dSPNs. To investigate if the neonatal spontaneous activity is needed for the stabilization of SPN long-range projections, we chemogenetically inhibited striosomal SPNs in neonatal animals and studied the efficiency of striatonigral projections in adult animals. Inhibition of striosomal SPNs by chronic CNO administration to P6-14 pups caused a reduction in the functional GABAergic innervation and in the density of gephyrin puncta in dopaminergic neurons of substantia nigra pars compacta of the adult (P52-79) animals. Chronic administration of CNO later in development (P21-29), on the contrary, resulted in higher mIPSC frequency in dopaminergic cells of the adult animals. Thus, the activity-dependent stabilization of striosomal projections has different developmental phases, and the long-term outcome of perturbations in these processes depends on the developmental period when they occur. Taken together, our results demonstrate that spontaneous activity of SPNs is essential for the maturation and stabilization of striatal efferents.

neuroscience↗

bioRxiv2019

PLANAR POLARIZATION OF CILIA IN THE ZEBRAFISH FLOOR PLATE INVOLVES Par3-MEDIATED POSTERIOR LOCALIZATION OF HIGHLY MOTILE BASAL BODIES.

To produce a directional flow, ciliated epithelia display a uniform orientation of ciliary beating. Oriented beating requires planar cell polarity (PCP), which leads to planar orientation and asymmetric positioning of the ciliary basal body (BB) along the polarity axis. We took advantage of the polarized mono-ciliated epithelium of the embryonic zebrafish floor plate to investigate by live-imaging the dynamics and mechanisms of BB polarization. We showed that BBs, although bearing a cilium, were highly motile along the antero-posterior axis. BBs contacted both the anterior and the posterior membranes, with a bias towards posterior contacts from early somitogenesis on. Contacts exclusively occurred at junctional Par3 local enrichments or "patches" and were often preceded by transient membrane digitations extending towards the BB, suggesting focused cortical pulling forces. Accordingly, BBs and Par3 patches were linked by dynamic microtubules. We showed that Par3 became posteriorly enriched prior to BB posterior positioning and that floor plate polarization was impaired upon Par3 patches disruption triggered by Par3 or aPKC overexpression. In the PCP mutant Vangl2, where floor plate cells fail to polarize, we observed that BB were still motile but presented behavioral defects, such as ectopic contacts with lateral membranes that correlated with Par3 patch fragmentation and spreading to lateral membranes. Our data lead us to propose an unexpected function for posterior local Par3 enrichment in controlling BB asymmetric positioning downstream of the PCP pathway via a microtubule capture/shrinkage mechanism.

developmental biology↗