Biology subjects

Cazzagon, G.

Publications and source records attributed to Cazzagon, G..

3 recordsLinked to original sources

bioRxiv2026

Genetically interacting mutations and mechanical stress affect the stochasticity of developmental eye defects in yap1 mutants

Congenital abnormalities of eye formation show remarkably variable penetrance with phenotypes even varying between left and right eyes. Here we explore this phenomenon through analysis of the mechanistic basis of low penetrance retinal coloboma in zebrafish yap1nl13/nl13 mutants and identification of factors that modify the probability of this phenotype. We find that the low penetrance stochastically occurring coloboma in yap1nl13/nl13 mutants is due to rupture in the ventral retina at the point of apposition of the lips of the closing choroid fissure and that provision of wild-type Yap in the retinal pigment epithelium suppressed this phenotype. Decreasing actomyosin contractility increased the penetrance of coloboma whereas increasing myosin phosphorylation rescued the phenotype suggesting that altered mechanical properties of the RPE sensitize the eye to stochastic failure of choroid fissure closure. Genetic interaction screening revealed enhanced and synthetic eye phenotypes in yap1nl13/nl13mutants upon abrogation of function of genes encoding extracellular matrix and other genes implicated in eye formation. Our data reveal that the variable penetrance of congenital eye abnormalities can be due to genetic and environmental factors impacting the stochastic variability inherent in the developmental processes underlying eye morphogenesis.

developmental biology↗

bioRxiv2023

SCAR and the Arp2/3 complex polarise the actomyosin cortex and plasma membrane organization in asymmetrically dividing neuroblasts

While the Formin-nucleated actomyosin cortex has been shown to drive the changes in cell shape that accompany cell division in both symmetric and asymmetric cell divisions, it is not clear whether or not Arp2/3-nucleated branched actin filament networks also play a role. In order to look for mitotic roles of the Arp2/3 complex, here we use Drosophila neural stem cells as a model system. These cells are unusual in that they divide asymmetrically to produce a large and small daughter cell with different fates. Our analysis identifies a pool of Arp2/3-dependent actin-based membrane protrusions that form at the apical cortex of these cells as they enter mitosis. Strikingly, at metaphase, these protrusions co-localise with components of the SCAR complex. By perturbing Arp2/3 complex activity we show that this apical pool of actin likely functions to limit the accumulation of apical Myosin in metaphase. Following the onset of anaphase, the loss of these SCAR and Arp2/3 dependent structures then leads to a delay in the clearance of apical Myosin and to cortical instability at cytokinesis. These data point to a role for a polarised branched actin filament network in fine tuning the apical actomyosin cortex to enable the precise control of cell shape during asymmetric cell division.

cell biology↗

bioRxiv2019

Podoplanin function is switched by partner proteins on fibroblastic reticular cells

Lymph node expansion is pivotal for adaptive immunity. CLEC-2+ migratory dendritic cells (DCs) interact with fibroblastic reticular cells (FRCs) to inhibit podoplanin-dependent actomyosin contractility, permitting FRC spreading and lymph node expansion. However, the molecular mechanisms controlling lymph node remodelling are not fully understood. We asked how podoplanin is regulated on FRCs in the early phase of lymph node expansion in vivo, and further, which other FRC markers are required for FRCs to respond to CLEC-2+ DCs. We find that expression of podoplanin and its partner proteins CD44 and CD9 in FRCs is coregulated by CLEC-2, and is differentially expressed by specific lymph node stromal populations in vivo. We find that beyond contractility, podoplanin is required for polarity and alignment of FRCs. Both CD44 and CD9 act to dampen podoplanin-dependent contractility, and colocalize with podoplanin in different areas of the cell membrane. Independently of podoplanin, CD44 and CD9 affect the degree of cell-cell contact and overlap between neighbouring FRCs. Further, we show that both CD44 and CD9 are required for FRCs to spread and form protrusions in response to DCs. Our data show that remodelling of the FRC cytoskeleton is a two-step process requiring podoplanin partner proteins CD44 and CD9. Firstly, CLEC-2/podoplanin-binding drives relaxation of actomyosin contractility, and secondly FRCs form protrusions and spread which requires both CD44 and CD9. Together, we show a multi-faceted response of FRCs to DCs, which requires CD44 and CD9 in addition to podoplanin.

cell biology↗