Mutation of an upstream cleavage site in the BMP4 prodomain leads to tissue-specific loss of activity
2006
ProBMP4 is initially cleaved at a site adjacent to the mature ligand (the
S1 site) allowing for subsequent cleavage at an upstream (S2) site. Mature
BMP4 synthesized from a precursor in which the S2 site cannot be cleaved
remains in a complex with the prodomain that is targeted for lysosomal
degradation, and is thus less active when overexpressed in Xenopus .
Here we report that mice carrying a point mutation that prevents S2 processing
show severe loss of BMP4 activity in some tissues, such as testes and germ
cells, whereas other tissues that are sensitive to Bmp4 dosage, such
as the limb, dorsal vertebrae and kidney, develop normally. In a
haploinsufficient background, inability to cleave the S2 site leads to
embryonic and postnatal lethality due to defects in multiple organ systems
including the allantois, placental vasculature, ventral body wall, eye and
heart. These data demonstrate that cleavage of the S2 site is essential for
normal development and, more importantly, suggest that this site might be
selectively cleaved in a tissue-specific fashion. In addition, these studies
provide the first genetic evidence that BMP4 is required for dorsal vertebral
fusion and closure of the ventral body wall.
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