Role of the Polycystins in Cell Migration, Polarity, and Tissue Morphogenesis - PubMed (original) (raw)

Review

Role of the Polycystins in Cell Migration, Polarity, and Tissue Morphogenesis

Elisa Agnese Nigro et al. Cells. 2015.

Abstract

Cystic kidney diseases (CKD) is a class of disorders characterized by ciliary dysfunction and, therefore, belonging to the ciliopathies. The prototype CKD is autosomal dominant polycystic kidney disease (ADPKD), whose mutated genes encode for two membrane-bound proteins, polycystin-1 (PC-1) and polycystin-2 (PC-2), of unknown function. Recent studies on CKD-associated genes identified new mechanisms of morphogenesis that are central for establishment and maintenance of proper renal tubular diameter. During embryonic development in the mouse and lower vertebrates a convergent-extension (CE)-like mechanism based on planar cell polarity (PCP) and cellular intercalation is involved in "sculpting" the tubules into a narrow and elongated shape. Once the appropriate diameter is established, further elongation occurs through oriented cell division (OCD). The polycystins (PCs) regulate some of these essential processes. In this review we summarize recent work on the role of PCs in regulating cell migration, the cytoskeleton, and front-rear polarity. These important properties are essential for proper morphogenesis of the renal tubules and the lymphatic vessels. We highlight here several open questions and controversies. Finally, we try to outline some of the next steps required to study these processes and their relevance in physiological and pathological conditions.

Keywords: cell migration; cell polarity; cilia; epithelial morphogenesis; planar cell polarity; polycystic kidney disease; polycystin; renal cyst.

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Figures

Figure 1

Figure 1

Apical-basal and Planar Polarity in Epithelia. Schematic representation of an epithelium, showing an apical-basal polarity along the vertical axis (a) and a planar cell polarity along the orthogonal axis (b); their appearance in association is shown in a tubular structure (c).

Figure 2

Figure 2

Main developmental steps of the renal nephron. Branching of the ureter generates ureteric buds (UB), surrounded by mesenchymal tissue (a); their interaction induces a mesenchymal-to-epithelial transition and generates the renal vescicle (b); that develops in a patterned comma-shaped body (c); subsequently extending in a tubular S-shaped body (d). On one side the S-shaped body makes contact with the ureter, on the other side it connects with migrating endothelial cells that will form the vascular loop within the glomerulus. The patterned expression of specific transcription factors in each tract of the S-shaped body generates the different structures of the mature nephron (see color code (e)).

Figure 3

Figure 3

Narrowing and elongation of developing renal tubules and collecting ducts. During embryonic development, the S-shaped body tubular structure (a) elongates and establish its diameter in a proliferation-independent manner: because cells intercalate perpendicularly to the longitudinal axis, the tubule becomes narrower and longer without changing cell number (b,c); in post-natal phases, the longitudinal orientation of cell division allows to maintain the diameter and to increase length of the tubule (d,e). During cell intercalation, cells resolve from a horizontal status to a vertical one passing through an intermediate cross-shaped state (f) When re-shaping involves a larger number of cells, the intermediate status displays a rosette profile (g).

Figure 4

Figure 4

The Polycystins in Cell Migration. PC-1 and PC-2 are involved in different pathways and functional roles, among these they were reported to inhibit apoptosis, proliferation, and growth. Furthermore, they are known to regulate calcium homeostasis. All these processes were shown to be deregulated in ADPKD. Additional functions of the PCs more recently reported involve regulation of cell migration and tissue morphogenesis. The involvement of these last two functions in the disease remains unclear (see text) (a); schematic summary showing the cellular effects of the PCs in cell migration and front-rear polarity in wound-healing assays [5,6,8,74]. PC-1 regulates the actin and microtubular cystoskeleton and the turnover rates of FAs and AJs and affecting both the rates of cell migration and front-rear polarity (b); at a single cell level MDCKII cells appear asymmetrical, whereas overexpression of PC-1 induces elongation and cellular asymmetry with a polarized actin cytoskeleton (red) and the Golgi (green) re-positioned in front of the nucleus (blue) (c).

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