Figure 1.

Signalling events in involution. Milk stasis induces the expression of leukaemia inhibitory factor (LIF) and transforming growth factor (TGF)β3 within 12 hours of forced weaning. These, in turn, phosphorylate and activate the transcription factor Stat3. This results in the induction of apoptosis and shedding of dying cells into the alveolar lumen. Neighbouring cells migrate to close the gap and maintain the integrity of the alveolar structure. Concurrently with these events, members of the death receptor ligand family and their receptors are transcriptionally upregulated and this induces apoptosis through activation of caspase 8. Downstream targets of these pathways are then induced and ensure the transition to the second phase. Following this reversible first phase, matrix metalloproteases (MMP) begin to break down the ECM surrounding each alveolus, resulting in detachment induced apoptosis and collapse of the alveoli. Remodelling is then completed by re-differentiation of the adipoctyes which requires the action of plasmin and MMP3. Full involution returns the gland to a pre-pregnant state. ECM, extracellular matrix.