a, Schematic representation of the conditional allele, with loxP sites (red triangles) flanking exon 18. The reading frame of each exon is indicated below the corresponding square, as x–x. Deletion of exon 18 leads to a frame-shift introducing a premature stop codon (indicated by amino acids in red). The resulting protein lacks the critical HEAT domains that are conserved in NIPBL and SCC2 proteins. b, c, Embryonic day 12 (E12) embryos (b) and E18 fetuses (c) carrying the conditional Nipbl allele (Nipblflox) and either ubiquitous (Hprt:Cre45) or limb-specific (Prx1::Cre46) Cre recombinase drivers. Structures expressing Cre are rapidly lost in Nipblflox/flox animals. Heterozygous Nipblflox/+ animals are grossly morphologically normal, but die soon after birth, as reported for other Nipbl loss of function alleles68. Fl, forelimb; md, mandible; abw, abdominal wall. d, e, Histochemical staining of liver section of adult ΔNipbl mouse (Nipblflox/flox; Ttr::CreERT2; 10 days after tamoxifen injection) for a proliferation marker (Phos-H3) (d) and apoptosis (cleaved Caspase3) (e) (both shown in red). Nuclei are stained with DAPI (blue). Staining was performed once.