Comparing the Bbs10 complete knockout phenotype with a specific renal epithelial knockout one highlights the link between renal defects and systemic inactivation in mice
- Noëlle Cognard†1, 2,
- Maria J Scerbo†1,
- Cathy Obringer†1,
- Xiangxiang Yu1,
- Fanny Costa1,
- Elodie Haser1,
- Dane Le1,
- Corinne Stoetzel1,
- Michel J Roux3,
- Bruno Moulin2,
- Hélène Dollfus1, 4 and
- Vincent Marion1Email author
© Cognard et al. 2015
Received: 13 January 2015
Accepted: 20 July 2015
Published: 13 August 2015
Bardet–Biedl Syndrome (BBS) is a genetically heterogeneous ciliopathy with clinical cardinal features including retinal degeneration, obesity and renal dysfunction. To date, 20 BBS genes have been identified with BBS10 being a major BBS gene found to be mutated in almost 20 percent of all BBS patients worldwide. It codes for the BBS10 protein which forms part of a chaperone complex localized at the basal body of the primary cilium. Renal dysfunction in BBS patients is one of the major causes of morbidity in human patients and is associated initially with urinary concentration defects related to water reabsorption impairment in renal epithelial cells. The aim of this study was to study and compare the impact of a total Bbs10 inactivation (Bbs10 −/−) with that of a specific renal epithelial cells inactivation (Bbs10 fl/fl ; Cdh16-Cre +/−).
We generated the Bbs10 −/− and Bbs10 fl/fl ; Cadh16-Cre +/− mouse model and characterized them. Bbs10 −/− mice developed obesity, retinal degeneration, structural defects in the glomeruli, polyuria associated with high circulating arginine vasopressin (AVP) concentrations, and vacuolated, yet ciliated, renal epithelial cells. On the other hand, the Bbs10 fl/fl ; Cadh16-Cre +/−mice displayed no detectable impairment.
These data highlight the importance of a systemic Bbs10 inactivation to trigger averted renal dysfunction whereas a targeted absence of BBS10 in the renal epithelium is seemingly non-deleterious.
KeywordsBardet–Biedl Syndrome Bbs10 Total knockout Retinal degeneration Obesity Renal epithelial-specific KO
Bardet–Biedl syndrome (BBS)  is an autosomal recessive ciliopathy for which 20 genes (BBS1-20) have been identified to date. It is clinically characterized, among features, by early-onset retinitis pigmentosa (RP), obesity and renal dysfunction as well as polydactyly, RP is a rod–cone dystrophy , leading to progressive visual loss and blindness . The connecting cilium of photoreceptors, a highly specialized primary cilium [3, 4], plays a pivotal role in intraciliary transport (ICT) between the inner and outer segments . The established mechanism behind this phenotype is an excessive accumulation of protein in the inner segment (IS) of the photoreceptor due to defect in intracellular transport (ICT) [6, 7] triggering an unfolded protein response-mediated apoptosis of the photoreceptors [8–10]. In parallel, obesity develops together with the RP  and is associated with hyperleptinemia. The high circulating concentrations of Leptin observed both in patients  and mouse models [12, 13] have historically been linked to a hypothalamic defect in the regulation of food intake leading to hyperphagia and decreased energy expenditure . More recently, BBS proteins have been shown to play a key role in the adipose tissue maturation and function  which strongly suggest that multiple pathways could be driving the BBS-obese phenotype.
Compared to RP and obesity, BBS-induced renal impairment after birth tends to display a late-onset profile as it is generally detected in the late childhood. This major cause of morbidity and mortality for the BBS patients is characterized by an initial urinary concentrating defects associated with polyuria–polydypsia . Concomitantly, scores of structural abnormalities like small kidneys with normal or irregular contours and reduced parenchyma thickness, calyceal distortion, clubbing and blunting, caliectasis, presence of medullary cysts communicating or not with mildly dilated calyceal system and occasional presence of cortical cysts have been reported and they represent the full clinical spectrum of the BBS renal phenotype . To explain these BBS renal phenotypes several defective signalling pathways have been incriminated such as a defective WNT signalling cascade during development [17, 18] as well as the lack of ciliary targeting of the antidiuretic hormone arginine vasopressin (AVP) isoform 2 receptor (AVPR2). In combination to these intrinsic effects of BBS inactivation, it has been reported that the occurrence of obesity was a leading cause for the presence of renal cysts in mice; an effect which was reverted when they went through food restriction . Although the results highlight the difficulty in identifying the exact pathological mechanism leading to renal dysfunction in the BBS, in an attempt to understand the precise impact of BBS inactivation in the ciliated renal epithelium, we generated the Bbs10 −/− mice and the Bbs10 fl/fl ; Cadh16-Cre +/− and studied the resulting phenotypes.
Generation of Bbs10 total knockout mice and Bbs10 renal epithelial-specific knockout mice
All experimental procedures were approved by the local ethical committee of Strasbourg. See Additional file 1: Supporting information for supplementary methods. The inactivation of the Bbs10 gene was achieved by the deletion of the exon 2. Bbs10 fl/fl mice were obtained by DNA recombination, using LoxP sites flanking the 5′ and 3′ regions of the exon 2 in Bbs10 gene in embryonic stem cells line 129OLA using a neomycin cassette as a selectable marker (Additional file 2: Figure S1). These mice were bred with Cadh16-CreDeleter mice (B6.Cg-Tg (Cadh16-Cre) 91Igr/J, stock number 012237 from Jackson). Homozygous knockout mice Bbs10 −/− and the control littermates Bbs10 +/+ were obtained by mating of heterozygous Bbs10 +/−mice. Chimeric mice were obtained on a C57/BL6 genetic background. Bbs10 fl/fl mice were bred with the Ksp1.3/Cre transgenic mouse lines expressing heterozygous Cre recombinase gene under the control of a tissue-specific promoter: Ksp-Cadherin (Cadherin16), exclusively expressed in renal tubular epithelial cells . The resulting Bbs10 fl/fl ; Cadh16-Cre +/− together with the Bbs10 +/+ ; Cadh16-Cre +/− mice were generated. All the genotypes were checked by PCR using KAPA Mouse Genotyping Kit (#KK7302, Kapa Biosystems, Woburn, Massachusetts, USA). Primer sequences used for Bbs10 genotyping were 5′-ACA AAT ACA ATT GAT CAT CGA TGT G-3′ (forward primer) and 5′-GTT GCC TGG CTT GGG TGG CA-3′ (reverse primer), and 5′-ACC TCC CCA CTT GAA CGA GGT CT-3′ (forward) and 5′-GTT GCC TGG CTT GGG TGG CA-3′ (reverse) for WT and floxed mice. For Cadh16 Cre genotyping, the primer sequences used were 5′-GCA GAT CTG GCT CTC CAA AG-3′ as sense primer and 5′-AGG CAA ATT TTG GTG TAC GG-3′ as antisense primer, and 5′-CAA ATG TTG CTT GTC TGG TG-3′ (forward) and 5′-GTC AGT CGA GTG CAC AGT TT-3′ (reverse) for the internal positive control. Genotyping at the ROSA26 locus of the RosaTomato/eGFP (Gt(ROSA)26Sortm4(ACTB-tdTomato,−EGFP)Luo/J, Jackson Laboratories Stock # 007576) mice was performed using the following three-primer set: oIMR7318: 5′-CTC TGC TGC CTC CTG GCT TCT-3′; oIMR7319: 5′-CGA GGC GGA TCA CAA GCA ATA-3′; oIMR7320: 5′-TCA ATG GGC GGG GGT CGT T-3′. See Additional file 1: Supporting information for supplementary methods.
Molecular characterisation of the Bbs10 −/− mice
Bbs10 −/− mice display typical BBS-obese phenotype
Bbs10 −/− mice exhibit retinal degeneration
Structural renal abnormalities associated with functional impairment are observed in Bbs10 −/− mice
Bbs10 fl/fl ; Cadh16Cre +/− exhibit no detectable impairment in renal morphology or function
Systemic Bbs10 inactivation is a prerequisite for the classical polyuria phenotype in vivo
Herein, we describe and compare the phenotypes of a Bbs10 −/− versus Bbs10 fl/fl ; Cadh16Cre +/− mice. The Bbs10 −/− mice recapitulated most clinical features of the human condition, ranging from early-onset obesity, retinal degeneration and renal dysfunction whereas the Bbs10 fl/fl ; Cadh16Cre +/− mice show neither detectable renal defect at 3 months nor any other noticeable manifestations. The Cadh16 Cre mouse used in this work to mediate the specific inactivation of Bbs10 in renal epithelial cells was the Cre Ksp1.3/Cre transgenic mouse. This model carries the 1,329 bp fragments of the 5′ flanking region of the Ksp-cadherin promoter . Two Cadh16-Cre mice were developed by the group of Igarashi in 2002 containing different fragments of the 5′ flanking region of the Ksp-cadherin promoter , one of the mice carrying the 1,329 bp (Ksp1.3/Cre mouse) and the other carrying the 324 bp fragment (Ksp0.3/Cre mice). Cre expression in Ksp1.3 mice was restricted to the tubular epithelial cells in the mature and developing kidney, while the Ksp0.3 mice produce a variegated expression pattern [19, 22]. In this work we used the Ksp1.3/Cre transgenic mice to specifically target the tubular epithelial cells of the kidney and no other renal cells types. Based on the results presented here and combined with the use of the specified Cre mouse line, it seems that specific Bbs10 inactivation in the renal epithelium on its own, may not be sufficient to be deleterious to renal function up to 3 months. This being said, we cannot entirely exclude especially in absence of a phenotype in the Bbs10 fl/fl ; Cadh16Cre +/− that this lack of impact on the renal physiology could be due to a heterogeneous and variable activity of the Cre in vivo; a proof that will require further investigations.
On the other hand Bbs10 −/− mice developed progressive obesity associated with hyperphagia and hyperleptinemia. The absence of hypertrophic adipose tissue at 3 months in both Bbs10 −/− and Bbs12 −/− mice does not support the classical leptin resistance theory leading to obesity in the BBS (32). In fact, our results follow the same line of thought that was suggested by another group studying the Bbs4 −/− mice. The authors demonstrated that leptin resistance was not a constitutive defect but seemingly an acquired one appearing as the mice were ageing . Besides, we and others have also shown that the inactivation of BBS genes was favouring pre-adipocyte lineage [14, 23] and adipogenesis . These effects could explain the observed hyperplastic adipose tissue as well as the higher circulating levels of leptin observed in Bbs10 −/− mice (Fig. 2d); a phenotype observed in all BBS mouse models and in human patients (15, 16, 31, 30). Moreover, the 3-month-old Bbs10 −/− mice were not hyperglycaemic but exhibited a significant delay in bringing their glucose levels back to normal following GTT (Fig. 2f). Simultaneously, these mice showed insulin sensitivity, indicating that the delay in glucose handling observed with the GTT was not related to insulin resistance. Interestingly, it has been described that leptin could be as effective as insulin in controlling glucose levels . It is, therefore, conceivable that the delay in glucose handling observed in the Bbs10 −/− mice could be due to the hyperleptinemia; a hypothesis that warrants further investigations with targeted tissue BBS inactivation. In this present study, 3-month-old mice were used to clearly demonstrate that in absence of obesity Bbs10 inactivation has no major impact on renal function. Although it might seem interesting to have older mice to investigate the effect of Bbs10 inactivation at later stages, it then becomes difficult to dissect the exact contribution of Bbs inactivation due to the effects of ageing itself.
Coincidently, the Bbs10 −/− mice suffered from RP. The retinal degeneration observed in the Bbs10 −/− was similar to the other previous Bbs mouse models (33, 34, 29, 27, 19), characterized by the loss of photoreceptors resulting in a thinning of the retina and a progressive flattening of the ERGs. Of note, is the presence of connecting cilium (Fig. 3c). With the complete photoreceptor structure, the Bbs10 −/− retina highlights the fact that BBS10, as was the case for BBS12 , is not required for ciliogenesis. The observed defect is probably related to an impaired ICT from the inner segment to the outer segment.
BBS renal phenotype is a mix of different defects of the nephron correlating with the variable human renal phenotype. We, therefore, investigated the effect of a total knockout condition versus a specific renal epithelial inactivation. In the Bbs10 −/− mice, the glomeruli suffered from the absence of the primary and secondary podocyte structures (Fig. 4b) correlating with elevated albuminuria (Fig. 4c). Accordingly, no such glomerulopathy was present in the Bbs10 fl/fl ; Cadh16Cre +/− mice (Fig. 5f, g), as the Cre activity was limited to the renal epithelial regions (Figure S2B). The primary cilium is known to play a role in development of the podocytes and that later in life, the podocytes lose their ciliated status as the flow gets stronger to prevent excessive polycystin-mediated calcium signalling . As the observed structural defects in the Bbs10-deprived podocytes seemingly bear a developmental aspect and not an acquired one, we hypothesized that BBS10 is crucial for proper podocyte development. Surprisingly, human BBS patients do not present overt early-onset glomerulopathy but do exhibit decreasing glomerular function with age [28, 29]. This discrepancy could result from inherent differences between species as exemplified by the fact that rodent podocytes seem to be ciliated only during development  whereas human podocytes remain ciliated in fully differentiated and functional podocytes [30, 31].
Moreover, cyst was undetectable in both Bbs10 −/− and the Bbs10 fl/fl ; Cadh16Cre +/− kidneys (Figs. 4b–f, 5f–h and Additional file 5: Figure S4). This feature shared with other BBS chaperone KO mice, namely the Bbs12 −/−, suggests that chaperone BBS inactivation does not impact the planar cell polarization (PCP) of the developing kidney like other ciliopathies. In addition, proper PCP of the Bbs10-deprived renal epithelial cells was further evidenced by the presence of primary cilia on the apical side of the epithelium (Figs. 4e, 5d) combined with the AQP2 apical localisation (Figs. 4h, 5e). Interestingly, only Bbs2 −/− and Bbs4 −/− mice suffered from late-onset cystogenesis which was secondary and uniquely associated to obesity . Altogether, these data highlight that cyst formation is not, per se, intrinsically correlated to BBS gene inactivation but could nevertheless favour cystogenesis when combined with BBS-induced obesity. Besides cytoplasmic vacuoles, an established parameter for cellular stress of the renal epithelium  was observed in the Bbs10 −/− renal epithelial cells but not in the Bbs10 fl/fl ; Cadh16Cre +/− ones (Figs. 4g, 5h). These highlight the prerequisite of multiple defects to induce detectable renal defects.
Finally, polyuria, the most prominent human renal phenotype in BBS was observed in the Bbs10 −/− and not in Bbs10 fl/fl ; Cadh16Cre +/− mice. Given that AVPR2 is localized in the primary cilium of renal epithelial cells and that BBS protein inactivation in renal cells impairs their capacity to respond to AVP and activate their luminal AQP2 in vitro , we measured the protein levels of AQP2, AQP3 and AVPR2. No difference in expression levels of these proteins were found in both tested models. This indicates that polyuria in the Bbs10 −/− mice is not linked to a local decrease in expression levels of these proteins (Fig. 6b, c, f, g). The fact that the AVP levels were always high in the Bbs10 −/− mice, irrespective of the fluid intake condition (Fig. 6d), highlights an AVP-resistant status in Bbs10 −/− mice; an effect which was absent in the Bbs10 fl/fl ; Cadh16Cre +/− mice (Fig. 6h). Based on these findings, we hypothesized that the BBS-induced polyuria is not simply related to the absence of BBS10 in the renal epithelium but is the result of more complex interactions between several pathways being impacted in the Bbs10 −/−. These could be linked to the hypothalamic–pituitary axis sensing osmolality and secreting AVP compared to the other ciliated cells.
The data presented herein describe the phenotype of a new mouse model for one of the most commonly mutated genes in BBS human patients, namely BBS10, with special emphasis in the kidney phenotype. Our findings show that deletion of Bbs10 is able to recapitulate most of the clinical BBS features, whereas the Bbs10 fl/fl ; Cadh16Cre +/− did not induce any detectable defect. Overall, these results highlight once more the complexity of renal dysfunction characterizing this emblematic ciliopathy and like for the study of the origins of obesity, an integrative approach is required to understand and ultimately cure these genetic disorders.
Bardet–Biedl syndrome gene 10
glucose tolerance test
insulin tolerance test
outer nuclear layer
transmission electron microscopy
arginine, vasopressin receptor 2
NC performed the renal phenotyping experiments, the analysis of the data and wrote the paper, MJS performed the metabolic phenotyping, analysed the data and wrote the paper, XY, EH, CO, FC, DL generated the mice, performed the retinal phenotyping and the morphological phenotyping. CS performed the real-time experiments. MJR, BM and HD analysed the data, wrote the manuscript, VM conceived and coordinated the experiments, analysed the data and wrote the manuscript. All authors have been involved in drafting the manuscript and in its revision. All authors read and approved the final manuscript.
We thank the Mouse Clinic Institute for generating the Bbs10 fl/fl mouse model. We are grateful to Jean-Louis Mandel for his constant support and Eric Robinet from the Institute of Virology, INSERM_U1110 for all the technical support. This project was supported by the ANR Calls 2006, 2009, UNADEV, Retina France and by the National Institute for Health and Medical Research funding (INSERM).
Compliance with ethical guidelines
Competing interests The authors declare that they have no competing interests.
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