CUZD1 is a critical mediator of the JAK/STAT5 signaling pathway that controls mammary gland development during pregnancy

Abstract

In the mammary gland, genetic circuits controlled by estrogen, progesterone, and prolactin, act in concert with pathways regulated by members of the epidermal growth factor family to orchestrate growth and morphogenesis during puberty, pregnancy and lactation. However, the precise mechanisms underlying the crosstalk between the hormonal and growth factor pathways remain poorly understood. We have identified the CUB and zona pellucida-like domain-containing protein 1 (CUZD1), expressed in mammary ductal and alveolar epithelium, as a novel mediator of mammary gland proliferation and differentiation during pregnancy and lactation. Cuzd1-null mice exhibited a striking impairment in mammary ductal branching and alveolar development during pregnancy, resulting in a subsequent defect in lactation. Gene expression profiling of mammary epithelium revealed that CUZD1 regulates the expression of a subset of the EGF family growth factors, epiregulin, neuregulin-1, and epigen, which act in an autocrine fashion to activate ErbB1 and ErbB4 receptors. Proteomic studies further revealed that CUZD1 interacts with a complex containing JAK1/JAK2 and STAT5, downstream transducers of prolactin signaling in the mammary gland. In the absence of CUZD1, STAT5 phosphorylation in the mammary epithelium during alveologenesis was abolished. Conversely, elevated expression of Cuzd1 in mammary epithelial cells stimulated prolactin-induced phosphorylation and nuclear translocation of STAT5. Chromatin immunoprecipitation confirmed co-occupancy of phosphorylated STAT5 and CUZD1 in the regulatory regions of epiregulin, a potential regulator of epithelial proliferation, and whey acidic protein, a marker of epithelial differentiation. Collectively, these findings suggest that CUZD1 plays a critical role in prolactin-induced JAK/STAT5 signaling that controls the expression of key STAT5 target genes involved in mammary epithelial proliferation and differentiation during alveolar development.

Prolactin-Responsive Circular RNA circHIPK3 Promotes Proliferation of Mammary Epithelial Cells from Dairy Cow

“…The Jak-STAT signaling pathway is an essential pathway for PRL induction [35]. PRL can stimulate the STAT5 pathway to affect cell proliferation and differentiation [36]. In this study, we used the STAT5 inhibitor to verify the effect of prolactin on the expression of circHIPK3.…”

Regulation of the JAK2-STAT5 Pathway by Signaling Molecules in the Mammary Gland

“…Immunoprecipitation results show that CUZD1 forms a complex with JAK2 and STAT5, and CUZD1 FIGURE 1 | Novel components of the JAK2-STAT5 signaling pathway. CPAP, centrosomal P4.1-associated protein; CypA, cyclophilin A; CUZD1, zona pellucida-like domain-containing protein 1; JAK2, Janus kinase 2; NcoA, nuclear receptor co-activator; PIKE-A, PI 3-kinase enhancer A; PlrR, prolactin receptor; STAT5, signal transducers and activators of transcription 5. knockout disrupts the connection between JAK2 and STAT5 (Mapes et al, 2017). In addition, PIKE-A has also been reported to participate in complex formation with PRLR and STAT5, which is required for activation of the PRLR and STAT5 signaling pathways (Chan et al, 2010).…”

“…CUZD1 knockout abolishes STAT5 phosphorylation and impairs mammary ductal branching and alveolar development. However, CUZD1 overexpression in mammary epithelial cells increases STAT5 phosphorylation ( Mapes et al, 2017 ). Immunoprecipitation results show that CUZD1 forms a complex with JAK2 and STAT5, and CUZD1 knockout disrupts the connection between JAK2 and STAT5 ( Mapes et al, 2017 ).…”

New Insights of Mammary Gland During Different Stages of Development

“…The TGF-β family members play an important role in ductal differentiation and branching morphogenesis; besides their involvement in malignant ductal tissue patterning [76]. It is observed that the protein termed CUB and zona pellucida-like domain-containing protein 1 mediates its function to control gland development through JAK2-STAT5 pathway during conception [77]. The IGF1 is essential for lobule and alveoli development [78].…”