BMP-binding protein twisted gastrulation is required in mammary gland epithelium for normal ductal elongation and myoepithelial compartmentalization

Abstract

Bone morphogenetic proteins (BMPs) are involved in embryonic mammary gland (MG) development and can be dysregulated in breast cancer. However, the role BMPs play in the postnatal MG remains virtually unknown. BMPs are potent morphogens that are involved in cell fate determination, proliferation, apoptosis and adult tissue homeostasis. Twisted gastrulation (TWSG1) is a secreted BMP binding protein that modulates BMP ligand availability in the extracellular space. Here we investigate the consequences of TWSG1 deletion on development of the postnatal MG. At puberty, Twsg1 is expressed in the myoepithelium and in a subset of body cells of the terminal end buds. In the mature duct, Twsg1 expression is primarily restricted to the myoepithelial layer. Global deletion of Twsg1 leads to a delay in ductal elongation, reduced secondary branching, enlarged terminal end buds, and occluded lumens. This is associated with an increase in luminal epithelial cell number and a decrease in apoptosis. In the MG, pSMAD1/5/8 level and the expression of BMP target genes are reduced, consistent with a decrease in BMP signaling. GATA-3, which is required for luminal identity, is reduced in Twsg1−/− MGs, which may explain why K14 positive cells, which are normally restricted to the myoepithelial layer, are found within the luminal compartment and shed into the lumen. In summary, regulation of BMP signaling by TWSG1 is required for normal ductal elongation, branching of the ductal tree, lumen formation, and myoepithelial compartmentalization in the postnatal MG.

Molecular liaisons between erythropoiesis and iron metabolism

“…17 In vitro, high concentrations of GDF15 or TWSG1 suppressed hepcidin expression in primary hepatocytes or hepatocyte cell lines. 14,15 However, the role of GDF15 and TWSG1 in hepcidin suppression in vivo is less clear.…”

TGF-β Family Signaling in Ductal Differentiation and Branching Morphogenesis

“…In the absence of BMP-4, the mammary buds fail to develop fully and their branching morphogenesis is perturbed (Hens et al 2007). BMPs also promote mammary ductal morphogenesis at later stages, as is apparent by studies of the extracellular BMP ligand accessory protein, twisted gastrulation (Twsg) (Forsman et al 2013). Twsg is expressed Morphogenesis of a ductal tree in the mammary gland proceeds with epithelial cell proliferation, which is inhibited by TGF-b1, TGF-b3, and activins (TGF-b2 is not well-expressed during breast morphogenesis), by blocking hepatocyte growth factor (HGF), growth hormone (GH), estrogen (ES), and insulin-like growth factor 1 (IGF-1) expression and activities.…”

“…only in myoepithelial cells and in a few cells of the developing bud (Forsman et al 2013). Inactivation of the Twsg gene in mice causes a dramatic block in branching morphogenesis and terminal alveolar lumen differentiation (Forsman et al 2013).…”

Erythroferron: Modern Concepts of Its Role in Iron Metabolism Regulation

“…Несмотря на то что оба этих белка синтезируются в различных тканях, в моделях ex vivo показана их экспрессия на поздней (GDF15) и ранней (TWSG1) стадиях дифференцировки эритробластов человека. В патогенезе воспаления, онкологических и сердечно-сосудистых заболеваний, ожирения [11] GDF15 играет роль через не полностью изученные механизмы, в то время как TWSG1 модулирует актив-ность костного морфогенетического белка в период эмбрионального развития и во многих тканях взрослых людей [12]. В условиях in vitro установлено, что высокие концентрации GDF15 или TWSG1 по-давляют экспрессию гепсидина в клеточных линиях гепатоцитов [9,10].…”