Abstract
ABSTRACTThe Golgi-associated RAB GTPases, RAB6A and RAB6A′, regulate anterograde and retrograde transport pathways from and to the Golgi. In vitro, RAB6A/A′ control several cellular functions including cell division, migration, adhesion and polarity. However, their role remains poorly described in vivo. Here, we generated BlgCre; Rab6aF/F mice presenting a specific deletion of Rab6a in the mammary luminal secretory lineage during gestation and lactation. Rab6a loss severely impaired the differentiation, maturation and maintenance of the secretory tissue, compromising lactation. The mutant epithelium displayed a decreased activation of STAT5, a key regulator of the lactogenic process primarily governed by prolactin. Data obtained with a 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 upon Rab6a deletion, 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 and suggest that the trafficking pathways controlled by RAB6A/A′ depend on cell-type specialization and tissue context.
Highlights
Small GTPases of the RAB family are master regulators of vesicular transport and membrane trafficking in eukaryotic cells
We have shown that RAB6A/A′ is required for the proper maturation of melanosomes in melanocytes and that they play a key role in T lymphocyte activation (Patwardhan et al, 2017; Carpier et al, 2018)
Loss of Rab6a severely compromised the lactational function of the gland and the maintenance of the secretory tissue
Summary
Small GTPases of the RAB family are master regulators of vesicular transport and membrane trafficking in eukaryotic cells. Through their specific intracellular localization and ability to recruit various types of effectors, RAB GTPases tightly control the molecular exchanges between cell compartments (Stenmark, 2009). In human, this large family comprises about 70 members which include four RAB6 proteins, RAB6A and its splice variant RAB6A′, RAB6B and RAB6C. The ubiquitously expressed RAB6A/A′ are the most abundant Golgi-associated RAB GTPases and have been reported to. RAB6A/A′ null mouse embryos die at day 5.5, exhibiting defective adhesion between the epiblast layer and the visceral endoderm, with a disorganization of the basement membrane and a perturbed expression of the β1 integrin chain in epiblast cells (Shafaq-Zadah et al, 2016)
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