Fig. 4: Attenuated positional effects in polCA carrying a pathogenic FGFR3 mutation.

a, Schematic representing the position of glycine-to-arginine substitution (violet) at codon 380 located in the transmembrane domain (TM) of the Fgfr3 protein. S, sulfur bond, TK1/TK2, intracellular tyrosine kinase domains 1/2. b, Representative images of 15 div conCAs, polCAs and polCAs^MUT at proximal and distal positions stained with hematoxylin and eosin on top, or DAPI, EdU and PH3 on the bottom. Scale bars, 50 µm. c,d, Fraction of EdU⁺ cells (c) and PH3⁺ cells (d) normalized to total (DAPI⁺) cells in proximal and distal insets of conCAs, polCAs and polCAs^MUT at 15 div. In c, n = 33 insets for proximal conCAs, n = 35 insets for distal conCAs, proximal polCAs and distal polCAs^MUT, n = 36 insets for distal polCAs and proximal polCAs^MUT. In d, n = 12 insets for proximal and distal conCAs, n = 35 insets for proximal polCAs and distal polCAs^MUT, n = 36 insets for distal polCAs and proximal polCAs^MUT. Data are from 3 organoids per condition, 2 slices per organoid. P values resulting from one-way ANOVA (Tukey’s multiple-comparisons test) are available (**** P < 0.0001). e, PCA plot of control (CTRL), polCAs and mutant polCAs (polCA^MUT) samples using VST expression values of the top 500 most variably expressed genes. The two datasets have been merged with RUVseq batch correction. f, Top loading of the PCA shown in e. g, Heat map showing corrected and row-centered gene expression of the same rostrally or caudally enriched genes from Fig. 3e, across the mutant dataset and ordered by complete linkage clustering.

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