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Borges, A.

Publications and source records attributed to Borges, A..

3 recordsLinked to original sources

Size matters: an analytical study on the role of tissue size in spatiotemporal distribution of morphogens unveils a transition between different reaction-diffusion regimes

The reaction-diffusion model constitutes one of the most influential mathematical models to study distribution of morphogens in tissues. Despite its widespread use, the effect of finite tissue size on model-predicted spatiotemporal morphogen distributions has not been completely elucidated. In this study, we analytically investigated the spatiotemporal distributions of morphogens predicted by a reaction-diffusion model in a finite 1D domain, as a proxy for a biological tissue, and compared it with the solution of the infinite-domain model. We explored the reduced parameter, the tissue length in units of a characteristic reaction-diffusion length, and identified two reaction-diffusion regimes separated by a crossover tissue size estimated in [~]3.3 characteristic reaction-diffusion lengths. While above this crossover the infinite-domain model constitutes a good approximation, it breaks below this crossover, whereas the finite-domain model faithfully describes the entire parameter space. We evaluated whether the infinite-domain model renders accurate estimations of diffusion coefficients when fitted to finite spatial profiles, a procedure typically followed in Fluorescence Recovery After Photobleaching (FRAP) experiments. We found that the infinite-domain model overestimates diffusion coefficients when the domain is smaller than the crossover tissue size. Thus, the crossover tissue size may be instrumental in selecting the suitable reaction-diffusion model to study tissue morphogenesis.

systems biology

Eya1-dependent homeostasis of morphogenetic territories during collective cell migration

Mutations in the transcriptional co-activator Eya1 cause branchio-oto-renal syndrome (BOR) in humans, and the equivalent conditions in vertebrates. BOR has an incidence of 1/40,000 and is characterized by congenital branchial fistulas, malformations of the inner ear and kidney hypoplasia. Therapeutic interventions for BOR are currently limited to reparative surgery, hearing aids and dialysis. Here we use the mechanosensory lateral line in zebrafish to better understand the role of Eya1 in organogenesis. The lateral line develops from a primordium formed by approximately 150 cells that move together from head to tail of the embryo at a constant velocity. This invariant migration occurs over a trail of Sdf1a chemokine and is controlled by the simultaneous action of two receptors. The CXCR4b is expressed in the front half of the primordium where it acts as a chemokine sensor, whereas the CXCR7b is present in the rear half, serving as a chemokine sink to ensure persistent directionality. We show that the loss of Eya1 strongly reduces the expression of CXCR7b, disrupting the coherent motion of the primordium and leading to lateral-line truncations. We also find evidence of reduced epithelial maturation in primordia lacking Eya1. These findings argue for abnormal collective cell chemotaxis as the origin of organ dysmorphia in BOR.

developmental biology

Direct observation of genome surveillance by CRISPR-Cas in bacteria

CRISPR-Cas systems are prokaryotic adaptive immune systems that have been well characterized biochemically, but in vivo spatiotemporal regulation and cell biology remains largely unaddressed. Here, we used fluorescent fusion proteins to study the localization of the Type I-F CRISPR-Cas system native to Pseudomonas aeruginosa. When targeted to an integrated prophage, the crRNA-guided (Csy) complex and a majority of Cas3 molecules in the cell are recruited to a single focus. When lacking a target in the cell, however, the Csy complex is broadly nucleoid bound, while Cas3 is diffuse in the cytoplasm. Nucleoid association for the Csy proteins is crRNA-dependent, and inhibited by expression of anti-CRISPR AcrIF2, which blocks PAM binding. The Cas9 nuclease is also nucleoid localized, only when gRNA-bound, which is abolished by PAM mimic, AcrIIA4. Our findings reveal PAM-dependent nucleoid surveillance and spatiotemporal regulation in Type I CRISPR-Cas that separates the nuclease-helicase Cas3 from the crRNA-guided surveillance complex.

microbiology