Generation of a conditional Adamts6 mouse allele reveals roles in lung maturation in addition to cardiac and musculoskeletal development

Prior analysis of mouse embryos homozygous for a point mutation (p.Ser149Arg) that abrogated secretion of the protease, ADAMTS6, showed that it is essential for cardiovascular and limb development. Because <i>Adamts6</i> ^S149R/S149R mice do not survive past birth, it is currently not feasible to investigate ADAMTS6 in specific cellular lineages postnatally. Therefore, we generated a conditional allele using CRISPR-Cas9-mediated genome editing to insert unidirectional loxP sites flanking the first coding exon in <i>Adamts6</i>, resulting in a frameshift mutation after loxP recombination. Mice homozygous for the unrecombined floxed allele (<i>Adamts6</i> ^fl/fl) are viable, fertile, and without overt phenotype. <i>Adamts6</i> ^del/del embryos, generated upon constitutive recombination induced by a <i>CMV</i>-Cre transgene, also do not survive past birth and have identical defects in the heart and limbs as <i>Adamts6</i> ^S149R/S149R embryos, demonstrating efficient transgene recombination. In addition to previous defects in cardiovascular and limb development, <i>Adamts6</i> ^del/del embryos have reduced airway branching, thereby identifying a role for ADAMTS6 in lung maturation. This newly generated <i>Adamts6</i> ^fl allele makes feasible analysis of ADAMTS6 secreted by cells of different lineages and during specified temporal windows during developmental processes as well as in disease models.