Getwan M , Hoppmann A , Schlosser P , Grand K , Song W , Diehl R , Schroda S , Heeg F , Deutsch K , Hildebrandt F , Lausch E , Köttgen A , Lienkamp SS .

R01 DK068306 NIDDK NIH HHS

             cartilage development

                asphyxiating thoracic dystrophy
                ciliopathy
                polydactyly
                nephronophthisis
                cystic kidney disease
                kidney disease

           NEPHRONOPHTHISIS 1; NPHP1

Xla Wt + ift80 CRISPR (Sup. Fig. 1 e)
Xtr Wt + cep192 CRISPR (Sup. Fig. 5 c d )
Xtr Wt + cfap20 CRISPR (Sup. Fig. 5 c d)
Xtr Wt + ift172 CRISPR (Fig. 1 A bottom, 1 B right)
Xtr Wt + ift172 CRISPR (Fig. 1 C bottom, Sup. Fig. 1 g)
Xtr Wt + ift172 CRISPR (Fig. 1 D bottom)
Xtr Wt + ift172 CRISPR (Fig. 2 C)
Xtr Wt + ift172 CRISPR (Fig. 2 I J bottom)
Xtr Wt + ift172 CRISPR (Fig. 2 K bottom L)
Xtr Wt + ift172 CRISPR (Fig. 6 C D row 4, Sup. Fig. 7)
Xtr Wt + ift172 MO (Sup. Fig. 1 d)
Xtr Wt + ift70a CRISPR (Fig. 4 B C)
Xtr Wt + ift70a CRISPR (Fig. 4 D right)
Xtr Wt + ift70a CRISPR (Fig. 4 D, Sup. Fig. 5 f h)
Xtr Wt + ift70a CRISPR (Fig. 4 E)
Xtr Wt + ift70a CRISPR (Fig. 5 A B)
Xtr Wt + ift70a CRISPR (Fig. 5 C D)
Xtr Wt + ift70a CRISPR (Fig. 6 C D row 2, Sup. Fig. 7)
Xtr Wt + ift80 CRISPR (Fig. 1 A top, 1 B left)
Xtr Wt + ift80 CRISPR (Fig. 1 C middle, Sup. Fig. 1 g)
Xtr Wt + ift80 CRISPR (Fig. 1 D middle)
Xtr Wt + ift80 CRISPR (Fig. 2 B)
Xtr Wt + ift80 CRISPR (Fig. 2 I J middle)
Xtr Wt + ift80 CRISPR (Fig. 6 C D row 3, Sup Fig. 7)
Xtr Wt + ift80 CRISPR (Fig. K middle, L)
Xtr Wt + ift80 MO (Sup. Fig. 1 d)

	Fig. 1. CRISPR targeting of ift80 and ift172 leads to skeletal defects in X. tropicalis. (A and B) Analysis of edema formation in ift80 and ift172 crispants at stage 42. Note the smaller eyes in ift80-targeted embryos. (C) Limb phenotypes in postmetamorphic froglets (stage 62/63). MicroCT scans of representative crispant froglets of slc45a2 (negative control), ift80, and ift172 revealed cartilage accumulations in CRISPR-targeted froglets (green arrowheads). Injections of RNPs were performed unilaterally (Left) at the 2-cell stage. Polydactyly is indicated by orange arrowheads that mark black nailed digits. In the corresponding 3-dimensional reconstructions, limb muscles are shown in red, eyes in yellow, and red arrowheads point to the affected limbs. sgR L: left-sided sgRNA injection, R: right, L: left. (D) Histological sections of hindlimbs were stained with hematoxylin-eosin. R: resting zone; Pr: proliferating zone; PH: prehypertrophic zone; and H: hypertrophic zone. (E) The length of uninjected (green dots) versus injected (red dots) limbs of the same individual are plotted (gray lines). ns: (not significant); *P P P A) 0.5 mm, (C) 5 mm, and (D) 200 µm.]
	fig. 2. Cystic kidney disease and cilia defects in ift80 and ift172 CRISPR–targeted X. tropicalis. (A–C) CRISPR/Cas9 targeting of slc45a2, ift80, and ift172 were performed unilaterally in two-cell–stage embryos. Mesonephroi of stage 61 to 63 froglets were analyzed by microCT scans and kidneys and cysts (red arrowheads in B and C) were segmented for 3D volumetric analysis; red: cysts on the injected side; green: uninjected side). (D) The number of cysts (>0.2mm), (E) the ratio of total cyst volume to kidney volume, and (F) the kidney volume (excluding cysts) was calculated and compared with kidneys of control injected animals. (G) Whole-mount in situ hybridization detects ift80 and ift172 in the multiciliated nephrostomes of the pronephros in stage 36 to 38 X. laevis. (H) Schematic depiction of the embryonic renal system of Xenopus. (I and J) Excretion assay with fluorescein-dextran at stage 38 to 40. Blue arrowheads point to the proximal part of the pronephros. Yellow arrowheads indicate fluorescence signal in the distal tubule, lacking on the injected side (J). A: anterior, P: posterior; excr: excreting; and emb: embryos. (K) Confocal images of multiciliated epidermal cells (MCCs) stained against acetylated tubulin (cyan). Centrin-RFP fusion protein served as a lineage marker (red arrowheads) and indicates CRISPR-targeted MCCs. Blue arrowheads point to nontargeted (wild type) cells. (L) The ciliated area was determined for each cell. Error bars indicate SEM. P > 0.05 ns (not significant); *P P P A–C) 1 mm, (G and I) 0.5 mm, and (L) 10 µm.]
	Fig. 3. In silico screening for candidates with similar properties to SC genes. (A) Schematic of the in silico screen. Known SC disease genes served as an input list. Resource lists represent datasets from various published screening approaches and were tested for enrichment of genes contained in the input list genes. Genes in significantly enriched resource lists were then scored based on membership or rank. The gene scores were statistically validated by an empirical P value based on 10 million random drawings of input list. (B) Whole-mount in situ hybridizations for four candidate genes (c11orf74, cep192, cfap20, and ttc30a) that were experimentally followed up are shown for tadpoles at stage 31 to 35 (nephrostome expression enlarged) and limb buds (stage 55 to 57). (Scale bars, 0.5 mm.) p, posterior; a, anterior; pr, proximal; and d, distal.
	Fig. 4. ttc30 loss of function resembles the SC-phenotype. (A) Phylogenetic tree of protein sequences of TTC30A/B orthologs in various species. Genetic duplication events are marked by red squares. (B) CRISPR targeting of ttc30a at the one-cell stage led to edema formation in stage 41 tadpoles, quantified in (C). Coinjection of ttc30a mRNA partially rescued the phenotype. (D) Unilaterally CRISPR-targeted ttc30a froglets developed shortened limbs on the injected side (green arrowhead). MicroCT analysis, 3D reconstructions, and histological sections stained with hematoxylin-eosin demonstrated accumulation of cartilage (green arrowhead). Quantification of limb length reduction of ttc30a targeted compared with nontargeted side. (E) MicroCT scans show cystic kidneys in ttc30a-targeted animals (red arrowhead). 3D reconstruction of the kidneys and cysts (red) were used for volumetric analysis. Quantifications of cyst number, the ratio of total cyst volume to kidney volume, and total kidney volume (excluding cysts). [Scale bars, (B) 0.5 mm, (D and E, 3D reconstruction) 2 mm, (D, histological section) 200 µm.] R, right; L, left; P, proximal; D, distal. P > 0.05 ns (not significant); *P P P
	Fig. 5. Single cell RNA-Sequencing analysis of Ttc30a/b-positive cells in developing mouse limbs. (A and B) Excretion assay of slc45a2 sgRNA–injected controls and ttc30a-targeted embryos. Blue arrowheads point to the proximal tubule, and yellow arrowheads highlight fluorescent dextran in the distal tubules as a measure of excretion. (C) Confocal images of epidermal MMCs of stage-36 embryos. centrin-RFP (red) marks cells targeted for ttc30a (red arrowheads). Blue arrowheads label wild-type cells. Cilia are stained with acetylated gamma-tubulin (cyan). (D) Quantification of ciliated area per cell in slc45a2 and ttc30a CRISPR–targeted cells. Error bars indicate SEM. P > 0.05 ns (not significant); *P P P E) Clustering of scRNA-Seq data from E15.5 mouse limbs into 10 different cell clusters using typical marker genes. (F) Detection of Ttc30b expression in respective cell clusters. (G) Comparison of percentage of cells per cluster expressing Ttc30a1, Ttc30a2, Ttc30b, Ift80, and Ift172. (H) Expression level of Ttc30b, Ift80, and Ift172 in respective tissue clusters. [Scale bars, (A) 0.5 mm and (C) 10 µm.] GP, growth plate.
	Fig. 6. Ttc30a affects posttranslational tubulin modifications and ciliary compartmentalization. (A) Glycylation (cyan) in combination with acetylation (red) and (B) glutamylation (cyan) of pronephric and neural tube cilia were detected by immunostaining in wild-type embryos at stage 39. Cells of the pronephros and neural tube were visualized by Lectin staining (white/gray). White arrowhead points to ventral cilia of the neural tube, and red arrowhead to primary cilia of the pronephric tubular system. Stainings of the nephrostomes and tubular system are also shown as single channels. L, lateral; M, medial; D, dorsal; V, ventral; gly, glycylation; lec, lectin; glu, glutamylation; and acet, acetylation. Influence of targeting ift80, ift172, and ttc30a by CRISPR/Cas9 on glycylation (C) and glutamylation (D) was analyzed by immunostainings of epidermal cilia at stage 36 (glutamylation/glycylation, cyan; acetylation, red). (E and F) A schematic model for the role of ttc30a during bone and kidney development. (E) Ttc30a interacts with Kif17 in the cilium and is crucial for tubulin modifications (blue, glycylation; red, glutamylation; and yellow, acetylation) (15, 92, 112). Mutations of ttc30a in Xenopus reduce acetylation and glycylation, negatively impact cartilage differentiation, and result in kidney cysts (F). Green, intraflagellar transport (IFT)-B proteins; red circled, known SC genes; gray, ciliary tubulin. Error bars indicate SEM. P > 0.05 ns (not significant); *P P P
	Supplementary Figure 1: Speci city controls of ift80 and ift172 CRISPR/Cas9 targeting experiments (a) Gene structure of X. tropicalis ift80 and ift172 with introns (lines) and exons (boxes). sgRNA-binding-sites are marked by a red arrow. (b, c) CRISPR editing analysis for ift80 and ift172. The site of the expected cut is depicted by black vertical lines in Sanger Sequencing chromatograms, the sgRNA binding site is marked in blue and the PAM site in red. (d) Knockdown of ift80 and ift172 using anitsense morpholino oligonucleotides resulted in edema formation in X. tropicalis. (e) CRISPR targeting of ift80 and ift172 in X. laevis also leads to edema formation. (f) In situ hybridization detected expression of ift80 and ift172 in limb buds of X. laevis (black arrowhead). p - posterior; a - anterior; pr - proximal; d - distal (g) Categorization of mutant froglets according to phenotypic strength of limb malformations. Error bars indicate SEM. p>0.05 ns (not signi cant); p<0.05 *; p<0.01 **; p<0.001 ***; Scale bars represent 0.5mm.
	Supplementary Figure 3: Phenotypic analysis of ift80 and ift172 targeted embryos. (a, b) Expression analysis of ift80 and ift172 by whole mount in situ hybridization in st. 26/27 embryos. The magnified images show a spotty pattern on the epidermis. (c, d) Expression analysis of aplnr, nkx2.5, prox1, nkcc2 and sglt1 of X. tropicalis (c) and X. laevis (d) unilaterally CRISPR targeted tadpoles. The bar graphs indicate a stronger (gray) or weaker (black) signal on the injected side. (e, f) Tomato-Lectin stain visualizes the pronephric tubules in unilaterally CRISPR targeted stage 39 tadpoles. Measurements of the bounding box area of the proximal tubule was not different between the injected side of the embryo and the wildtype half in each case. (g) Quantification of centrioles of epidermal MCCs after injection of centrin-RFP mRNA together with sgRNAs and Cas9. There was no significant difference in centriole number in CRISPR targeted cells. Error bars indicate SEM. p>0.05 ns (not significant); p<0.05 *; p<0.01 **; p<0.001 ***; Scale bars represent 0.5mm
	Supplementary Figure 4: RNA-Seq analysis of ift80 and ift172 targeted embryos. (a) Schematic representation of the RNA and DNA extraction protocol used for RNA-Seq experiments. Embryos were genotyped before sending puri ed RNA for sequencing (see “materials and methods” for detailed description). (b) Indel- and knockout scores from ICE for experimental replicates used in the RNA-Seq experiment. (c) Scatterplot of the log2-fold changes in mRNA expression between ift80- and ift172 targeted embryos. Signi cantly changed transcripts are labeled with gene names. Red dots mark genes exclusively altered in ift80- or ift172 targeted embryos. Green dots indicate genes signi cantly changed in both conditions. Blue arrowheads point to genes for which an association with the hedgehog signaling pathway has been described, orange arrowheads on genes with wnt-associations. (d, e) Vulcano-plots of RNA-Seq analysis of ift80 and ift172 targeted embryos show that the targeted genes were downregulated ef ciently in the respective experiments (red arrowheads).
	Supplementary Figure 4: RNA-Seq analysis of ift80 and ift172 targeted embryos. (f) A table of respective associations and references thereof. (g) In situ hybridization for differentially expressed genes in the RNA-Seq screen. Col1a1 expression is shown for X. laevis, all others for X. tropicalis tadpoles. (h, i) In situ hybridization of tissue marker genes was examined in X. tropicalis (h) and X. laevis (i) after unilateral CRISPR targeting of ift80 and ift172. The quantifications indicate a stronger (gray) or weaker (black) signal on the injected side. No obvious changes were found, only the snail expression, marking cranial neural crest streams, appeared to be fused in ift80 and ift172 targeted embryos.
	Supplementary Figure 4: RNA-Seq analysis of ift80 and ift172 targeted embryos. (k) Table of resource lists in which the candidate genes occurred. Scale bars represent 0.5mm.
	Supplementary Figure 5: Analysis of SC-associated candidate genes (a) Gene structure of X. tropicalis ttc30a with introns as lines and exons as boxes. The sgRNA target site is marked by a red arrow. (b) Genotyping and ICE analysis of ttc30a targeted embryos (sgRNA binding site - blue; PAM - red; cutting site - vertical black line). (c, d) Percentage of embryos developing edema after targeting c11orf74, cfap20 and cep192. Targeting of cfap20 resulted in significant edema formation, and was rescued by co-injection of cfap20 mRNA. Targeting cep192 resulted in signi cant edema formation, but at low percentages. (e) Percentage of edema formation in embryos injected at the one cell state in parallel to the animals raised to the froglet stage were used as ef cacy control. (f) An example of a ttc30a mutant froglet with polydactyly (orange arrowheads) and both fore- and hindlimb malformations (red arrowheads). Embryos were injected at the 2-cell stage into the right blastomere with sgRNA targeting ttc30a and Cas9. (g) Examples of unilaterally cep192 and cfap20 targeted animals without an obvious phenotype. (h) Quanti cation of limb defects of unilaterally targeted froglets. Shortened limbs were only detected in ttc30a targeted animals. Error bars indicate SEM. p>0.05 ns (not signi cant); p<0.05 *; p<0.01 **; p<0.001 ***; Scale bars represent (d) 0.5mm, (f, g) 5mm, magni cation 1mm.
	Supplementary Figure 6: scRNA-Seq data analysis of embryonic mouse limb buds. (a) tSNE plot of all identi ed cell clusters in scRNA-Seq data of E15.5 mice limbs. (b, c) Marker genes used to de ne the clusters. Gene expression is indicated in blue on the tSNE-plot. (c) Violin plots of respective marker transcript levels across the assigned tissue clusters. (d) Expression of Ift80, Ift172, Ttc30a1 and Ttc30a2 depicted in blue in the tSNE plot. (e) Expression levels of Ttc30a1 and Ttc30a2 in the tissue clusters.
	Supplementary Figure 7: In uence of IFT B components on PTMs (a, d) Integrated density of glycylation or glutamylation respectively was calculated in relation to acetylation of cilia. Values were normalized to the controls. (b, e) Mean intensities of acetylation and glutamylation or glycylation respectively were calculated for affected MCCs. (c, f) Area measurements demonstrating the amount of multicilia per CRISPR/Cas9 targeted cell. Error bars indicate SEM. p>0.05 ns (not signi cant); p<0.05 *; p<0.01 **; p<0.001 ***
	ift80 (intraflagellar transport 80) gene expression in a X. laevis embryo, assayed via in situ hybridization NF stage 35-38, lateral view, anterior left, dorsal up.
	ift172 (intraflagellar transport 80) gene expression in a X. laevis embryo, assayed via in situ hybridization NF stage 35-38, lateral view, anterior left, dorsal up.
	iftap (intraflagellar transport associated protein) gene expression in a X. laevis embryo, assayed via in situ hybridization NF stage 31-36, lateral view, anterior left, dorsal up.
	ift70a (intraflagellar transport 70a) gene expression in a X. laevis embryo, assayed via in situ hybridization NF stage 31-36, lateral view, anterior left, dorsal up.
	cacng1 (calcium channel, voltage-dependent, gamma subunit 1) gene expression in a X. tropicalis embryo, assayed via in situ hybridization NF stage 29-40, lateral view, anterior left, dorsal up.
	ccng1 (cyclin G1) gene expression in a X. tropicalis embryo, assayed via in situ hybridization NF stage 29-40, lateral view, anterior left, dorsal up.
	dscaml1 (Down syndrome cell adhesion molecule like 1) gene expression in a X. tropicalis embryo, assayed via in situ hybridization NF stage 29-40, lateral view, anterior left, dorsal up.
	olfm4 (olfactomedin 4) gene expression in a X. tropicalis embryo, assayed via in situ hybridization NF stage 29-40, lateral view, anterior left, dorsal up.
	riok3 (RIO kinase 3) gene expression in a X. tropicalis embryo, assayed via in situ hybridization NF stage 29-40, lateral view, anterior left, dorsal up.
	ulk1 (unc-51 like autophagy activating kinase 1) gene expression in a X. tropicalis embryo, assayed via in situ hybridization NF stage 29-40, lateral view, anterior left, dorsal up.

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