Consistent with lysosomal accumulation occurring only in homozygotes, heterozygotes remain susceptible to tuberculosis. Here, using a zebrafish Gaucher disease model, I find that the mutation GBA1 N370S, predominant among Ashkenazi Jews, increases resistance to tuberculosis through the microbicidal activity of glucosylsphingosine in macrophage lysosomes. It has been proposed that the underlying mutations confer a selective advantage, in particular conferring protection against tuberculosis. This and other lysosomal diseases occur with high frequency in Ashkenazi Jews. Finally, we discuss nuances that ought to be considered moving forward and the importance of future investigation in these emerging fields for application in other fields pertinent to adhesion-based processes.īiallelic mutations in the glucocerebrosidase (GBA1) gene cause Gaucher disease, characterized by lysosomal accumulation of glucosylceramide and glucosylsphingosine in macrophages. In this review, we review studies of cell-substrate adhesion machinery in organisms evolutionary distant from Metazoa and cover the current understanding and ongoing work on how focal adhesions function in single and collective cell migration in an in vivo environment, with an emphasis on work that directly visualizes cell-substrate adhesions. Furthering investigation in these areas is necessary to bolster our understanding of the role cell-substrate adhesion machinery across Eukaryotes plays during cell migration in physiological contexts such as cancer and pathogenesis. Though these studies provide a valuable foundation to the cell-substrate adhesion field, the evolution of cell-substrate adhesion machinery across evolutionary space and the role of focal adhesions in vivo are largely understudied within the field. Much of our understanding of focal adhesions, however, is primarily derived from in vitro studies in Metazoan systems. One of the most well-studied structures cells use to adhere to the ECM is focal adhesions, which are composed of a multilayered protein complex physically linking the ECM to the intracellular actin cytoskeleton. Cell adhesion to an extracellular matrix (ECM) generates traction forces necessary for efficient migration. Scale bars, 2 μm (d, left), 20 μm (j), 50 μm (d, right) or 0.5 mm (a,g).Ĭell-substrate adhesion is a critical aspect of many forms of cell migration. For b, e, h and k, individual data points, mean and s.d. For a, b, e, h and k, n indicates the number of embryos. Note, controls are lamc1+/+ and lamc1–/+ embryos. k, Quantification of the Cxcr4b–Kate-to-memGFP ratio in the primordia of embryos shown in j. j, Images of the Cxcl12a sensor in primordia of cxcl12a–/– and cxcl12a–/– lamC1–/– live embryos with clones in the muscle of the trunk that express mCherry or Cxcl12a. i, Illustration of the principle of the Cxcl12a sensor. h, Quantification of the distance migrated by the primordium in the indicated experimental conditions at 32 h.p.f. Asterisks indicate the ear and arrowheads the primordium. embryos with clones in the trunk muscle that express mCherry (not shown) or Cxcl12a together with mCherry (not shown). g, Images of the migrating primordium in cxcl12a–/– and cxcl12a–/– lamC1–/– 32 h.p.f. f, Schematic of the strategy used to express Cxcl12a in a few muscle cells in lamC1–/– embryos and siblings. e, Quantification of collagen IV filaments in control and lamC1–/– embryos. Right: antibody staining against collagen IV (Col IV) in control and lamC1–/– embryos. d, Left: TEM images of the ultrastructure of the BM between the skin and the muscle in control (n = 2) and lamC1–/– embryos (n = 1). n = cell speeds from more than 7 primordia with each more than 100 cells. The solid line indicates the median, whereas the dashed line indicates the quartile. c, Speed of Ctnna1-depleted primordium cells. b, Quantification of the migration distance for primordia shown in a. Close-up of the region is indicated by a dashed square. Primordium migration requires an intact BMĪ, Control and Ctnna1-depleted primordia (arrowheads) in 48 h.p.f.
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