Figure 2.

Molecular control of alveolar morphogenesis. Signalling from the progesterone receptor (Pgr) and prolactin receptor (Prlr) is essential for alveolar morphogenesis in pregnancy. Increases in serum progesterone (Pg) and prolactin (Prl) result in luminal cell proliferation during early pregnancy, which continues throughout gestation. (a,b) Heterogenous receptor patterning is essential for complete alveolar morphogenesis. (a) Transforming growth factor (Tgf)-β1 signalling via phosphorylation of Smad results in the transcription of target genes, which act to control proliferation in steroid receptor positive cells. Wnt4 and RankL are transcribed in response to Pgr signalling, probably in cooperation with Prl signalling, and appear to stimulate proliferation of neighbouring cells via paracrine mechanisms. (b) RankL binds to its receptor Rank in a neighbouring cell and activates the RankL/nuclear factor (NF)-κB pathway, resulting in cyclin-D1 (Ccnd1) transcription and proliferation. Wnt4 binds and activates its target β-catenin, which has specific roles for both luminal and myo-epithelium for cell fate decisions involving both proliferation and differentiation. (a,c) Prl binds to Prlr and activates the Jak2/Stat5 cascade, resulting in the transcription of genes, including various transcription factors (TF) involved in epithelial morphogenesis and branching (Wnt4), establishment of epithelial polarity and cell-cell interactions (claudins and connexins), stromal epithelial interactions (collagen and laminin), proteins that regulate their own pathway (Socs1/2) and lactation (serotonin and milk proteins). Prl signalling also results in the transcription of cyclin D1 via an insulin growth factor 2 dependent mechanism. The ets transcription factor Elf5, transcribed in response to Prl, can completely compensate for the loss of Prlr signalling. Laminin in the extracellular matrix binds to β1-integrin when contact between the basement membrane and the luminal epithelium is established, and is essential for the maintenance of alveolar cell polarity and differentiation. ErbB4 and its ligands complement Prlr signalling as activation of ErbB4 results in Stat5 phosphorylation and translocation to the nucleus. GJ, gap junction; L, lipid droplet; TJ, tight junction.