Bilder, D. | Search bioRxiv

bioRxiv2018

3D Tissue elongation via ECM stiffness-cued junctional remodeling

Organs are sculpted by extracellular as well as cell-intrinsic forces, but how collective cell dynamics are orchestrated in response to microenvironmental cues is poorly understood. Here we apply advanced image analysis to reveal ECM-responsive cell behaviors that drive elongation of the Drosophila follicle, a model 3D system in which basement membrane stiffness instructs tissue morphogenesis. Through in toto morphometric analyses of WT and round egg mutants, we find that neither changes in average cell shape nor oriented cell division are required for appropriate organ shape. Instead, a major element is a reorientation of elongated cells at the follicle anterior. Polarized reorientation is regulated by mechanical cues from the basement membrane, which are transduced by the Src tyrosine kinase to alter junctional E-cadherin trafficking. This mechanosensitive cellular behavior represents a conserved mechanism that can elongate edgeless tubular epithelia in a process distinct from those that elongate bounded, planar epithelia.

developmental biology↗

bioRxiv2017

High-risk Autism Spectrum Disorder Utah pedigrees: a novel Shared Genomic Segments analysis.

Progress in gene discovery for Autism Spectrum Disorder (ASD) has been rapid over the past decade, with major successes in validation of risk of predominantly rare, penetrant, de novo and inherited mutations in over 100 genes (de Rubies et al., 2015; Sanders et al., 2015). However, the majority of individuals with ASD diagnoses do not carry a rare, penetrant genetic risk factor. In fact, recent estimates suggest that most of the genetic liability of ASD is due to as yet undiscovered common, less penetrant inherited variation (Gaugler et al., 2014) which is much more difficult to detect. The study of extended, high-risk families adds significant information in our search for these common inherited risk factors. Here, we present results of a new, powerful pedigree analysis method (Shared Genomic Segments--SGS) on three large families from the Utah Autism Research Program. The method improves upon previous methods by allowing for within-family heterogeneity, and identifying exact region boundaries and subsets of cases who share for targeted follow-up analyses. Our SGS analyses identified one genome-wide significant shared segment on chromosome 17 (q21.32, p=1.47x10-8). Additional regions with suggestive evidence were identified on chromosomes 3, 4, 6, 8, 11, 13, 14, 15, and 18. Several of these segments showed evidence of sharing across families. Genes of interest in these regions include ATP8A1, DOCK3, CACNA2D2, ITGB3, AMBRA1, FOLH1, DGKZ, MTHFS, ARNT2, BTN2A2, BTN3A1, BTN3A3, BTN2A1, and BTN1A1. We are exploring multiple other lines of evidence to follow up these implicated regions and genes.

genetics↗