Semaphorin-Plexin Signaling Controls Mitotic Spindle Orientation during Epithelial Morphogenesis and Repair

Abstract

Morphogenesis, homeostasis, and regeneration of epithelial tissues rely on the accurate orientation of cell divisions, which is specified by the mitotic spindle axis. To remain in the epithelial plane, symmetrically dividing epithelial cells align their mitotic spindle axis with the plane. Here, we show that this alignment depends on epithelial cell-cell communication via semaphorin-plexin signaling. During kidney morphogenesis and repair, renal tubular epithelial cells lacking the transmembrane receptor Plexin-B2 or its semaphorin ligands fail to correctly orient the mitotic spindle, leading to severe defects in epithelial architecture and function. Analyses of a series of transgenic and knockout mice indicate that Plexin-B2 controls the cell division axis by signaling through its GTPase-activating protein (GAP) domain and Cdc42. Our data uncover semaphorin-plexin signaling as a central regulatory mechanism of mitotic spindle orientation necessary for the alignment of epithelial cell divisions with the epithelial plane.

ZO-1 interactions with F-actin and occludin direct epithelial polarization and single lumen specification in 3D culture

“…8A,B). Because previous studies have linked defective mitotic spindle orientation directly to the multi-lumen phenotype (Durgan et al, 2011;Hao et al, 2010;Jaffe et al, 2008;Qin et al, 2010;Rodriguez-Fraticelli et al, 2010;Xia et al, 2015;Zheng et al, 2010), we relied on the strong phenotype of single-versus multi-lumen cyst formation as both a morphogenetic indicator and marker of early polarization processes -e.g. spindle orientation.…”

Semaphorins and Plexins in Kidney Disease

“…In addition to class-3-semaphorins, the adult kidney expresses several class-4-semaphorins [13,14,21] (table 1). While Sema4A, 4B and 4D are found on renal TECs, Sema4C is expressed in the interstitium, and the localization of Sema4G is not known.…”

“…Different forms of glomerulonephritis can be classified according to their pathogenesis, their histological features and their clinical course. Sema4D is expressed by T-cells as well as in kidney tubules [12,13,14] (table 1), and global inactivation of the Sema4D gene has beneficial effects in different mouse models of glomerulonephritis including attenuated glomerular injury and less deposition of immunoglobulins in the glomeruli [12,15] (fig. 2b).…”

A basal cell defect promotes budding of prostatic intraepithelial neoplasia

“…A 3D model for prostate glands contains basal and luminal cell architecture Given the importance of the glandular structure for maintaining homeostasis (Brown, 2011;Chandramouly et al, 2007;Wilhelmsen et al, 2006;Xia et al, 2015) and the role of the basal cell stem cell compartment (Bonkhoff and Remberger, 1996;Bostwick, 1996b;Hudson, 2004;Karthaus et al, 2014;Schmelz et al, 2005), we generated a 3D model of prostate glands using two different primarily diploid prostate epithelial cell lines, RWPE-1 and PrEC 11220. RWPE-1 is a stable non-tumorigenic human cell line derived from a histologically normal adult human prostate Roh et al, 2008;Webber et al, 1997) and is used as a normal prostate cell line in genomic and differentiation studies (Wang et al, 2011;Webber et al, 1997).…”

“…During normal glandular development, extracellular matrix (ECM)-cell-receptor interaction provides contextual cues and a developmental 'morphogenesis checkpoint' for ordered repopulation (Brown, 2011). Cell divisions parallel to the basal cell surface maintain proximity to the ECM and control mitotic spindle orientation during epithelial morphogenesis and repair (Xia et al, 2015).…”