RAB6 GTPase is a crucial regulator of the mammary secretory function controlling STAT5 activation

The Golgi-associated RAB GTPases, RAB6A and RAB6A’, regulate anterograde and retrograde transport pathways from and to the Golgi.In vitro, RAB6A/A’ have been reported to be involved in several cellular functions, including, in addition to transport, cell division, migration, adhesion and polarity. However, their role remains poorly describedin vivo, in particular in epithelial tissues. Here, we generated BlgCre;Rab6aF/Fmouse presenting a specific deletion ofRab6ain the mammary luminal secretory lineage during gestation and lactation.Rab6aloss severely impaired the differentiation, maturation and maintenance of the secretory tissue, compromising lactation. It led to a decreased activation of STAT5, a key regulator of the lactogenic process primarily governed by prolactin. Data obtained with a human mammary epithelial cell line suggested that defective STAT5 activation might originate from a perturbed transport of the prolactin receptor, altering its membrane expression and signaling cascade. Despite the major functional defects observed uponRab6adeletion, the polarized organization of the mammary epithelial bilayer was preserved. Altogether, our data reveal a crucial role for RAB6A/A’ in the lactogenic function of the mammary gland. They also suggest that the trafficking pathways controlled by RAB6A/A’ depend on cell type specialization and tissue context.SUMMARY STATEMENTThis study reveals a role for the Golgi-associated RAB GTPases, RAB6A/A’, in the lactogenic function of the mammary gland.