BMP2/6 ligand formation and function in development and iron homeostasis
openNIDDK - National Institute of Diabetes and Digestive and Kidney Diseases
ABSTRACT
Bone morphogenetic proteins (BMPs) play critical roles in development and adult tissue homeostasis. Class I
(BMP2 and 4) and class II (BMP5-7) BMPs are the dominant players in specifying cell fate, embryonic patterning
and organ morphogenesis. We previously showed that liver endothelial cell (LEC)-derived BMP2 and BMP6 also
have a key role to regulate systemic homeostasis of the essential nutrient iron by controlling expression of the
liver hormone hepcidin. Indeed, iron homeostasis regulation is the major non-redundant function of BMP6 in
vivo, and impaired BMP signaling is the main cause of the iron overload disorder hereditary hemochromatosis.
BMPs are dimeric proteins that are made as precursors comprised of a non-signaling prodomain and an active
ligand released by proteolytic cleavage. Our work and others' have shown that prodomains play critical roles in
ligand folding, dimerization, activation, and receptor interactions. Moreover, many ligand functions are carried
out by heterodimers (comprised of 2 different ligands) rather than homodimers. Notably, little is known about
BMP2 or BMP6 dimerization, proteolytic processing, and prodomain function. Moreover, BMP6 prodomain
mutations are linked to altered hepcidin regulation and iron overload in humans, but the mechanisms are
uncertain. Here, we will show that 1) LEC-secreted BMP2 and BMP6 must work together to regulate hepcidin
and iron homeostasis in vivo; 2) co-expressed BMP2 and BMP6 form heterodimers that signal more strongly vs
homodimers; 2) BMP2 and BMP6 proteolytic maturation and/or subcellular trafficking differ from their closest
homologues BMP4 and BMP7; 3) BMP2 prodomain is essential to generate active BMP6 homodimers or BMP2/6
heterodimers in Xenopus embryos, whereas cognate prodomains are essential in LECs; and 4) BMP6 prodomain
mutations linked to iron overload impair ligand activity and hepcidin induction in vitro. We hypothesize that
BMP2/6 heterodimers are a key ligand for hepcidin and iron homeostasis regulation and that prodomains have
critical roles in BMP2/6 maturation and function. In this proposal, we aim to use structural modeling, Xenopus
embryos, a human LEC-hepatocyte cell culture system, and novel knock-in mice to elucidate how BMP2 and
BMP6 prodomains, and the process of proteolytic maturation, contribute to heterodimer and/or homodimer
formation and function, and how BMP6 prodomain mutations impact these processes to impair hepcidin
regulation and cause iron overload. Our long-term goals are to understand how BMP signaling is regulated to
control hepcidin expression and systemic iron homeostasis, how this process is perturbed in iron disorders, and
ultimately to develop new treatments for iron disorders. We will also gain fundamental insights into BMP ligand
maturation and prodomain function that will have broader impacts for many other fields where BMP signaling is
important, including developmental biology.
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health research