Efficient Mammary Gland Involution Requires c-Jun N-terminal kinase

Involution returns the lactating mammary gland to a quiescent state after weaning. The mechanism of involution involves collapse of the mammary epithelial cell compartment. To test whether the cJUN NH2-terminal kinase (JNK) signal transduction pathway contributes to involution, we established mice with JNK deficiency in the mammary epithelium. We found that JNK is required for efficient involution. JNK deficiency did not alter the STAT3/5 or SMAD2/3 signaling pathways that have been previously implicated in this process. Nevertheless, JNK promotes the expression of genes that drive involution, including matrix metalloproteases, cathepsins, and BH3-only proteins. These data demonstrate that JNK has a key role in mammary gland involution post lactation. WAP-Cre and Jnk1f/f Jnk2f/f WAP-Cre mice were bred for a single pregnancy and litters were normalized to 6-8 pups. The pups were allowed to nurse for 9 days before forced weaning. At that point, some mice were euthanized and their mammary glands were harvested to isolate RNA (0 days). Other mice were kept for 3 days before euthanasia and mammary gland harvest (3d). In this way, gene expression differences could be determined between JNK-null and JNK-wildtype mammary glands before and during involution.