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

Cynthia Forsman, Brandon C. Ng, Rachel K. Heinze, Claire Kuo, Consolato Sergi, Rajaram Gopalakrishnan, Douglas Yee, Daniel Graf, Kaylee Schwertfeger, Anna Petryk

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)95-106
Number of pages12
JournalDevelopmental Biology
Volume373
Issue number1
DOIs
StatePublished - Jan 1 2013

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Gastrulation
Bone Morphogenetic Proteins
Human Mammary Glands
Protein Binding
Carrier Proteins
Epithelium
Apoptosis
Extracellular Space
Puberty
Homeostasis
Cell Count
Epithelial Cells
Breast Neoplasms
Ligands

Keywords

  • BMP
  • Breast
  • Mammary gland development
  • Myoepithelium
  • TWSG1

Cite this

BMP-binding protein twisted gastrulation is required in mammary gland epithelium for normal ductal elongation and myoepithelial compartmentalization. / Forsman, Cynthia; Ng, Brandon C.; Heinze, Rachel K.; Kuo, Claire; Sergi, Consolato; Gopalakrishnan, Rajaram; Yee, Douglas; Graf, Daniel; Schwertfeger, Kaylee; Petryk, Anna.

In: Developmental Biology, Vol. 373, No. 1, 01.01.2013, p. 95-106.

Research output: Contribution to journalArticle

Forsman, Cynthia ; Ng, Brandon C. ; Heinze, Rachel K. ; Kuo, Claire ; Sergi, Consolato ; Gopalakrishnan, Rajaram ; Yee, Douglas ; Graf, Daniel ; Schwertfeger, Kaylee ; Petryk, Anna. / BMP-binding protein twisted gastrulation is required in mammary gland epithelium for normal ductal elongation and myoepithelial compartmentalization. In: Developmental Biology. 2013 ; Vol. 373, No. 1. pp. 95-106.
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