RAB6 GTPase regulates mammary secretory function by controlling the activation of STAT5

Abstract

The 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.

Rab6A as a Pan-Astrocytic Marker in Mouse and Human Brain, and Comparison with Other Glial Markers (GFAP, GS, Aldh1L1, SOX9)

“…The Rab6A antibody applied here has previously replicated this typical vesicular perinuclear staining in Chinese hamster ovary (CHO) cells [ 41 ]. To our knowledge, however, immunocytochemical localization of Rab6A or B in mammalian tissues has been determined only by very few studies (e.g., [ 25 , 39 , 41 , 42 , 43 ], see above), including the present one.…”

Developmental program‐independent secretory granule degradation in larval salivary gland cells of Drosophila

“…25 Moreover, several studies clearly show that absence of the endosome-to-TGN retrograde trafficking strongly perturbs the secretory process and directs proteins and lipids for lysosomal degradation. 27,[37][38][39]63 Notably, these factors are important research objects in this present study as well and were proven to also have a function in avoiding immature secretory granules from early acidification and crinophagic degradation.…”

“…35,36 Importantly, earlier studies clearly showed that components of the endosome-to-TGN retrograde transport, such as Vps52, Vps53 and Rab6 are also needed for normal secretory process. [37][38][39] Degradation of unnecessary, obsolete, or damaged secretory granules is required for maintaining homeostatic equilibrium in gland cells and tissues. There are several possibilities for their elimination, depending mainly on granule size.…”

“…Interestingly, fusion with the apical cell membrane and subsequent release of glue into the gland lumen require vesicle contraction, and the necessary force is mediated by an actin coat formation and recruitment of myosin around each vesicle 35,36 . Importantly, earlier studies clearly showed that components of the endosome‐to‐TGN retrograde transport, such as Vps52, Vps53 and Rab6 are also needed for normal secretory process 37–39 …”

Retrograde and Anterograde Transport of Lat-Vesicles during the Immunological Synapse Formation: Defining the Finely-Tuned Mechanism

“…In this study, we wanted to better characterize the role of molecules that we previously described as regulators of LAT recruitment to the immune synapse. This was particularly important for the small Rab GTPase Rab6, which has been shown to control both retrograde and anterograde transport of cargoes [ 23 , 24 , 42 , 43 , 44 ]. Yet, TIRF video-microscopy did not show any association of Rab6 and LAT at the activation sites ( Figure 3 A and Supplementary Video S3 ).…”