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Characterization of two novel knock-in mouse models of syndromic retinal ciliopathy carrying hypomorphic Sdccag8 mutations

Zhi-Lin Ren Hou-Bin Zhang Lin Li Zheng-Lin Yang Li Jiang

Zhi-Lin Ren, Hou-Bin Zhang, Lin Li, Zheng-Lin Yang, Li Jiang. Characterization of two novel knock-in mouse models of syndromic retinal ciliopathy carrying hypomorphic Sdccag8 mutations. Zoological Research, 2022, 43(3): 442-456. doi: 10.24272/j.issn.2095-8137.2021.387
Citation: Zhi-Lin Ren, Hou-Bin Zhang, Lin Li, Zheng-Lin Yang, Li Jiang. Characterization of two novel knock-in mouse models of syndromic retinal ciliopathy carrying hypomorphic Sdccag8 mutations. Zoological Research, 2022, 43(3): 442-456. doi: 10.24272/j.issn.2095-8137.2021.387

携带Sdccag8亚等位基因突变的两个视网膜纤毛病小鼠模型的表型特征

doi: 10.24272/j.issn.2095-8137.2021.387

Characterization of two novel knock-in mouse models of syndromic retinal ciliopathy carrying hypomorphic Sdccag8 mutations

Funds: This work was supported by the Natural Science Foundation of China (81670893, 82121003), Science and Technology Department of Sichuan Province (2021JDZH0031), and Chinese Academy of Medical Sciences (2019-I2M-5-032)
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  • 摘要: 虽早在十年前就从视网膜纤毛病家族中首次检出结肠癌血清学检测自身抗原蛋白8(SDCCAG8)基因突变,但仍不知其蛋白功能。为了开展SDCCAG8相关视网膜纤毛病致病机制的体内研究,我们利用CRISPR/Cas9介导的同源重组技术(HDR)成功构建携带Sdccag8截短突变的两个基因敲入小鼠模型,Sdccag8Y236X/Y236X Sdccag8E451GfsX467/E451GfsX467。它们所对应的人类SDCCAG8基因突变c.696T>G p.Y232X 和 c.1339–1340insG p.E447GfsX463分别致巴德毕式综合征(BBS)和洛肯综合征(SLS)两种视网膜纤毛病。两个基因敲入小鼠模型准确复制SDCCAG8相关BBS综合征的表型,包括视杆-视锥营养不良、肾囊肿、多趾畸形、不育和生长发育迟缓。其表型始发年龄和严重程度与Sdccag8突变的亚等位基因强度成正比。它们是迄今首次表现多趾畸形的BBS基因敲入小鼠模型。虽然,小鼠感光细胞发生退化后,主要光传导相关蛋白出现表达错位。但是,我们在突变小鼠的感光细胞、肾小管上皮细胞和小鼠胚胎成纤维细胞中都发现纤毛异常,提示SDCCAG8在纤毛发生中发挥着重要作用,纤毛异常是导致SDCCAG8相关视网膜纤毛病的根本原因。
  • Figure  1.  Generation of Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467 knock-in mice

    A: Schematic of two retinal ciliopathy-causing mutations, c.696T>G p.Y232X in exon7 and c.1339–1340insG p.E447GfsX463 in exon11, of human SDCCAG8 gene, and corresponding mouse Sdccag8 mutations c.708C>G p.Y236X and c.1351–1352insG p.E451GfsX467, respectively. B, C: Diagram of retinal ciliopathy-causing mutations Sdccag8-Y236X and Sdccag8-E451GfsX467 (indicated by “*”) inserted in mouse Sdccag8 gene by CRISPR/Cas9-mediated HDR with mutation-specific gRNAs and donor DNA oligos. Arrows show location of BamHI site next to each mutation and two pairs of PCR primers (Sdccag8-Y236X-F and -R, Sdccag8-E451GfsX467-F and -R) for mouse genotyping. D, E: DNA sequence traces of wild-type and two knock-in mice, Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467, showing successful introduction of mutation 708C>G and 1351–1352insG (in bold) and BamHI restriction site (underlined). F, G: Genotyping of knock-in mice by BamHI digestion of allele-specific PCR products. Sdccag8-Y236X mouse genotyping (F) shows 425 bp product from wild-type allele, and 258 bp and 170 bp products from Sdccag8-Y236X mutant allele. Sdccag8-E451GfsX467 mouse genotyping (G) shows 445 bp product from wild-type allele, and 263 bp and 186 bp products from Sdccag8-E451GfsX467 mutant allele.

    Figure  2.  Sdccag8 knock-in mice carrying a hypomorphic allele with growth retardation

    A: Immunoblot of mouse retinas at P30 for SDCCAG8 showing absence of full-length 83 kDa SDCCAG8 protein. Knock-in mice show expression of a 27 kDa SDCCAG8-Y236X or 54 kDa SDCCAG8-E451GfsX467 truncated protein at different hypomorphic levels. B: Immunoblot of transfected HEK293T cells for SDCCAG8 and GFP showing expression of GFP-tagged SDCCAG8 mutant proteins, 54 kDa EGFP-SDCCAG8 (Y236X), and 81 kDa EGFP- SDCCAG8 (E451GfsX467) at different hypomorphic levels. β-actin was used as a loading control. C: Immunohistochemical analysis of mouse retinas at P30 with anti-SDCCAG8 antibody (green), showing reduced expression levels of truncated proteins at photoreceptor CCs and ISs in two knock-in mouse lines. Scale bar: 20 µm. OS, outer segment; CC, connecting cilium; IS, inner segment; ONL, outer nuclear layer; INL, inner nuclear layer. D: Representative wild-type and Sdccag8Y236X/Y236X mice at P30, revealing serious growth retardation in knock-in mice that survived to birth. Scale bar: 1 000 µm. E: Body weight analysis of wild-type and knock-in mice at P30, showing significantly reduced body weight of Sdccag8Y236X/Y236X (9.33±1.21 g, n=6) and Sdccag8E451GfsX467/E451GfsX467 (10.50±1.38 g, n=6) mice compared to age-matched controls (17.67±1.37 g, n=6, ****: P<0.0001).

    Figure  3.  Retinal morphology of rod-cone photoreceptor degeneration in Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467 knock-in mice

    A–C: Histological analysis of wild-type and knock-in mouse retinas at P30 (A), P90 (B), and P180 (C) by H&E staining of retinal sections, displaying progressive shortening of ONL and OS in both knock-in mouse retinas, and noticeably earlier onset with increased severity in Sdccag8Y236X/Y236X mice. Scale bar: 20 µm. RPE, retinal pigment epithelium; OS, outer segment; IS, inner segment; ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer. D–F: Quantitative analysis of ONL thickness in wild-type and knock-in mouse retinas at P30, P90, and P180, showing progressive decrease in ONL thickness (nuclear number per row) in knock-in mouse retinas, which was more severe in Sdccag8Y236X/Y236X mice at all ages. Photoreceptor nuclei were counted at 500 µm increments from optic nerve. n=3–5. G: PNA-FITC lectin staining of wild-type and knock-in mouse retinas at P30, P90, and P180, revealing loss of cone cells initiated no earlier than P90 in both knock-in mice. Scale bar: 25 µm.

    Figure  4.  Scotopic and photopic electroretinograms (ERG) of rod-cone photoreceptor degeneration in Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467 mice

    A, B: Representative traces of scotopic (left) and photopic (right) ERG responses under 1.30 log cd·s/m2 light stimuli recorded from wild-type mice at P30, as well as Sdccag8Y236X/Y236X (A) and Sdccag8E451GfsX467/E451GfsX467 (B) mice at P30, P90, and P180, indicating progressive visual dysfunction of rods and cones in knock-in mice. C, D: Average a-wave amplitudes of scotopic ERG responses (C), and average b-wave amplitudes of photopic ERG responses (D) under 1.30 log cd·s/m2 light stimuli recorded from wild-type and knock-in mice at P30, P90, and P180, revealing rapid progressive visual dysfunction of photoreceptors with earlier onset in rods. n=3–7.

    Figure  5.  Immunolocalization of rod phototransduction-related proteins in Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467 mouse retinas

    Expression of membrane protein rhodopsin (A, B), as well as membrane-associated proteins rhodopsin kinase (GRK1) (C, D) and phosphodiesterase 6b (PDE6b) (E, F) in photoreceptor OS of wild-type and knock-in mouse retinas at P30 and P90, showing mislocalization of rhodopsin in photoreceptor IS and ONL in Sdccag8Y236X/Y236X retina at P90 (white arrows) and of GRK1 and PDE6b in IS, ONL, and synaptic terminals in two knock-in mouse retinas at P30 and P90 (white arrows). Scale bar: 20 µm (A–D), 25 µm (E–F).

    Figure  6.  Immunolocalization of cone phototransduction-related proteins in Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467 mouse retinas

    A–D: Expression of membrane protein S-opsin (A, B) and membrane-associated protein C-arrestin (C, D) in wild-type and knock-in mouse retinas, showing mislocalization in cone IS, cell body, and synaptic terminals in Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467 mice at both P30 and P90, except for S-opsin in Sdccag8E451GfsX467/E451GfsX467 mice at P30. Scale bar: 20 µm. C-arrestin, Cone arrestin. E: TUNEL staining of wild-type and knock-in mouse retinas at P21, revealing early-onset photoreceptor cell death in both knock-in mice. Scale bar: 30 µm.

    Figure  7.  Impaired cilia formation in photoreceptors and MEFs from Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467 mice

    A: Photoreceptor ultrastructure of wild-type and knock-in mice at P60, demonstrating shortened CC and disorganized OS with significantly deteriorated disk membrane in dying photoreceptors of Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467 mice. Scale bar: 1 µm. B: Immunofluorescence staining of serum-starved MEFs derived from wild-type and knock-in mice with anti-Ac-tubulin antibody (red) and nuclear dye DAPI (blue). Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467 MEFs showed shortened cilia compared to wild-type MEFs. Scale bar: 5 µm (bottom left) and 1 µm (bottom right). C, D: Analysis of cilium formation (C) and length (D) in serum-starved MEFs derived from wild-type and knock-in mice, showing significantly reduced cilium formation in Sdccag8Y236X/Y236X (8%) and Sdccag8E451GfsX467/E451GfsX467 (39%) MEFs, with decreased cilium lengths of 0.87±0.39 μm and 2.09±0.44 μm, respectively. In contrast, ~80% of wild-type MEFs grew cilia with an average length of 3.03±0.48 μm. n=100 for each genotype, ***: P<0.001; ****: P<0.0001.

    Figure  8.  Nephronophthisis in Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467 mice accompanied by defective renal cilia

    A: Representative kidneys dissected from wild-type and knock-in mice at P30, P90, and P180, showing moderate enlargement and deformation of kidneys in Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467 mice. Scale bar: 1 000 µm. B: H&E staining of kidney sections from wild-type and knock-in mice at P30, P90, and P180, displaying progressive development of tubular cysts and interstitial infiltrates in kidneys from both knock-in mice. Phenotype presented earlier and more severely in Sdccag8Y236X/Y236X mouse kidneys than in Sdccag8E451GfsX467/E451GfsX467 kidneys. Black arrows indicate glomerular cysts. Scale bar: 100 µm. C: Masson trichrome staining of wild-type and knock-in mouse kidneys at P30, P90, and P180, revealing more severe renal fibrosis in Sdccag8Y236X/Y236X mouse kidneys, and milder fibrosis in Sdccag8E451GfsX467/E451GfsX467 kidneys at P90 and P180. Scale bar: 100 µm. D: Immunohistochemical analysis of renal cilium formation in knock-in mice at P30, P90, and P180 with anti-acetylated tubulin (Ac-Tub) antibodies, showing progressive impairment of renal cilia in Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467 mice. Scale bar: 2 µm.

    Figure  9.  Preaxial polydactyly phenotype in Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467 mice

    A: Representative images of hind limbs of wild-type and knock-in mice, demonstrating preaxial polydactyly in hind limbs in Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467 mice, with 95%–100% penetrance. Digits are marked with Roman numerals from I to V starting from the thumb. Scale bar: 2 000 µm. B: Variable preaxial polydactyly phenotypes in knock-in mice, with predominance of bilateral polydactyly accounting for ~80% and 58% in Sdccag8Y236X/Y236X and Sdccag8E451GfsX467/E451GfsX467 mice, respectively.

    Table  1.   SDCCAG8 mutations identified in patients with retinal ciliopathies

    No.Mutation*Protein modificationLocation of mutationRetinal ciliopathyReferences
    1421-?_740+?del (hom)E141_R247del107fsExon5-7SLSOtto et al., 2010
    2679A>T (hom/het)K227XExon7BBS, SLSHalbritter et al., 2013b; Otto et al., 2010
    3696T>G (hom/het)Y232XExon7BBS, SLSHalbritter et al., 2013b; Otto et al., 2010
    4740_741ins741-202_741-1 (hom)R247SfsX270 (aberrant splicing)Intron7BBSShamseldin et al., 2020
    5740+356C>T (hom)ESE loss
    (aberrant splicing)
    Intron7BBS, SLSOtto et al., 2010; Tay et al., 2020
    6740+1delG (het)R247fsX250
    (aberrant splicing)
    Intron7BBSOtto et al., 2010
    7784G>T (het)E262XExon8SLSHalbritter et al., 2013b
    8845_848delTTTG (hom/het)C283XExon8BBS, SLSKang et al., 2016; Watanabe et al., 2019;
    Yamamura et al., 2017
    91068+1G>A (hom)Aberrant splicingIntron9BBSOtto et al., 2010
    101120C>T (hom)R374XExon10BBSSchaefer et al., 2011
    111221+2T>A (hom)Aberrant splicingIntron10BBSBahmanpour et al., 2020
    121300delA (het)N434IfsX462Exon11SLSKang et al., 2016
    131324dupC (het)Q442PfsX464Exon11SLSTay et al., 2020
    141339_1340insG (hom)E447GfsX463Exon11SLSOtto et al., 2010
    151420delG (hom)E474SfsX493Exon12SLSOtto et al., 2010
    161444delA (hom/het)T482SfsX493Exon12BBS, SLSBillingsley et al., 2012;
    Halbritter et al.,
    2013b; Otto et al., 2010
    171627_1630delGATA (het)D543AfsX566Exon14BBSBillingsley et al., 2012; Otto et al., 2010
    181796T>G (hom)L599XExon15SLSOtto et al., 2010
    191946_1949delGTGT (hom)C649SfsX658Exon16SLSOtto et al., 2010
    No.: Number. *: cDNA mutation numbering is based on human reference sequence NM_006642.5 for SDCCAG8, where +1 corresponds to A of ATG start translation codon. het: Heterozygous. hom: Homozygous. BBS: Bardet-Biedl syndrome. SLS: Senior-Løken syndrome.
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出版历程
  • 收稿日期:  2022-03-14
  • 录用日期:  2022-04-21
  • 网络出版日期:  2022-04-25
  • 刊出日期:  2022-05-18

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