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. 2016 Dec;90(6):1274-1284.
doi: 10.1016/j.kint.2016.07.011. Epub 2016 Sep 2.

Planar cell polarity genes Celsr1 and Vangl2 are necessary for kidney growth, differentiation, and rostrocaudal patterning

Hortensja Ł Brzóska  1 , Angela M d'Esposito  2 , Maria Kolatsi-Joannou  1 , Vishal Patel  3 , Peter Igarashi  4 , Yunping Lei  5 , Richard H Finnell  5 , Mark F Lythgoe  2 , Adrian S Woolf  6 , Eugenia Papakrivopoulou  7 , David A Long  8
Affiliations

Planar cell polarity genes Celsr1 and Vangl2 are necessary for kidney growth, differentiation, and rostrocaudal patterning

Hortensja Ł Brzóska et al. Kidney Int. 2016 Dec.

Abstract

The mammalian kidney contains nephrons comprising glomeruli and tubules joined to ureteric bud-derived collecting ducts. It has a characteristic bean-like shape, with near-complete rostrocaudal symmetry around the hilum. Here we show that Celsr1, a planar cell polarity (PCP) gene implicated in neural tube morphogenesis, is required for ureteric tree growth in early development and later in gestation prevents tubule overgrowth. We also found an interaction between Celsr1 and Vangl2 (another PCP gene) in ureteric tree growth, most marked in the caudal compartment of the kidneys from compound heterozygous mutant mice with a stunted rump. Furthermore, these genes together are required for the maturation of glomeruli. Interestingly, we demonstrated patients with CELSR1 mutations and spina bifida can have significant renal malformations. Thus, PCP genes are important in mammalian kidney development and have an unexpected role in rostrocaudal patterning during organogenesis.

Keywords: kidney development; planar cell polarity; renal malformations; rostrocaudal patterning; ureteric branching.

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Figures

Figure S1
Figure S1
Construction of a 3-dimensional skeletal structure from optical projection tomography images using Tree Surveyor software.
Figure S2
Figure S2
Uromodulin staining in wild-type, Celsr1Crsh/+, and Celsr1Crsh/Crsh kidneys. Note positive staining in all 3 genotypes (indicated by arrows). Bar = 75 μm, and images are representative of n = 4-6 for each genotype.
Figure S3
Figure S3
Apical membrane marker atypical protein kinase C (aPKCζ) staining in wild-type, Celsr1Crsh/+, and Celsr1Crsh/Crsh kidneys. Bar = 50 μm, and images are representative of n = 4-6 for each genotype.
Figure S4
Figure S4
Albumin excretion in 3-month-old wild-type (n = 7) and Celsr1Crsh/+ (n = 3) mice. There was no significant difference between the 2 groups.
Figure 1
Figure 1
Assessment of ureteric bud branching in mice with mutations in planar cell polarity genes. Images of whole metanephroi from E13.5 wild-type (a), Celsr1Crsh/+ (c), Celsr1Crsh/Crsh (e), Vangl2Lp/+ (g), and Celsr1Crsh/+:Vangl2Lp/+ (i) mice stained with calbindin-D28K and visualized by optical projection tomography. Branching networks of individual metanephroi from E13.5 wild-type (b), Celsr1Crsh/+ (d), Celsr1Crsh/Crsh (f), Vangl2Lp/+ (h), and Celsr1Crsh/+:Vangl2Lp/+ (j) mice. Data are representative of n = 3 for each genotype. Celsr1, Cadherin EGF LAG seven-pass G-type receptor 1; Vangl2, Van Gogh-like 2.
Figure 2
Figure 2
Quantitative assessment of ureteric bud branching in mice with mutations in planar cell polarity genes. Quantitative analysis of the total and caudal/rostral ratios of ureteric bud (UB) branch tips (a,b), number of “segments” (i.e., sections between branch points plus the tips) in the tree (c,d), and number of branch points in the tree (e,f) (n = 3 for each genotype). mRNA levels of Celsr1 (g) and Vangl2 (h) in the caudal versus the rostral compartment of E13.5 wild-type metanephroi (n = 6) as assessed by quantitative reverse transcriptase-polymerase chain reaction. Data are presented as mean ± SEM. *P < 0.05 and **P < 0.01 between groups. Celsr1, Cadherin EGF LAG seven-pass G-type receptor 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Vangl2, Van Gogh-like 2.
Figure 3
Figure 3
Histological analysis of E17.5 kidneys in mice with mutations in planar cell polarity genes. Low-power images of kidneys from E17.5 wild-type, Celsr1Crsh/+, Celsr1Crsh/Crsh, and Celsr1Crsh/+:Vangl2Lp/+ mice (a). There was clear demarcation between the cortex (c) and medulla (m) in kidneys from all genotypes except for Celsr1Crsh/+:Vangl2Lp/+ mice. Note the presence of dilated tubules (*) in Celsr1Crsh/Crsh kidneys. mRNA levels of Gdnf (b) and Ret (c) in E17.5 kidneys (n = 5–7) as assessed by quantitative reverse transcriptase-polymerase chain reaction. High-power images of the outer cortex of kidneys from wild-type (d), Celsr1Crsh/+ (e), and Celsr1Crsh/Crsh (f) mice containing glomeruli (g) and proximal tubules (pt) with PAS-positive material in their brush borders. Note dilated tubules (∗) in Celsr1Crsh/Crsh kidneys. Celsr1Crsh/+:Vangl2Lp/+ kidneys (g) contained immature glomeruli and rudimentary tubular structures. Measurement of proximal tubular diameter (h) in wild-type, Celsr1Crsh/+, Celsr1Crsh/Crsh, and Celsr1Crsh/+:Vangl2Lp/+ mice (n = 4–6). Examples of mitotic orientation measurements in tubules from E17.5 kidneys of wild-type (i) and Celsr1Crsh/Crsh mice (j). Quantification of mitotic orientation showing % of cells with specific angles of division (k) and average angle of division in tubular cells (l) (n = 3–5). Bar = 125 μm in (a), 50 μm in (d–g), and 15 μm in (i–j). *P < 0.05, **P < 0.01, and ***P < 0.001 between groups. Celsr1, Cadherin EGF LAG seven-pass G-type receptor 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PAS, periodic acid–Schiff; PCP, planar cell polarity; Vangl2, Van Gogh-like 2.
Figure 4
Figure 4
Assessment of glomeruli of E17.5 kidneys in mice with mutations in planar cell polarity genes. Representative images illustrating the 2 categories to which glomeruli were assigned: (a) Normal mature glomerulus and (b) immature glomerulus with <2 capillary loops. Quantification of glomerular morphology (c) showed a significant decrease in the proportion of normal glomeruli and an increase in the amount of immature glomeruli in Celsr1Crsh/+:Vangl2Lp/+ compared with wild-type mice. Assessment of tuft diameter (d) revealed no differences between any of the genotypes assessed. WT-1 and nephrin double immunostaining showed no difference in the glomerular expression pattern between wild-type, Celsr1Crsh/+, Celsr1Crsh/Crsh, and Celsr1Crsh/+:Vangl2Lp/+mice (e–h). Data are representative of n = 4–6. Bar = 50 μm in all panels. Data are presented as mean ± SEM. *P < 0.05 and **P < 0.01 between groups. Celsr1, Cadherin EGF LAG seven-pass G-type receptor 1; Vangl2, Van Gogh-like 2; WT-1, Wilms tumor-1.
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