Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects

Smad5 has been implicated as a downstream signal mediator for several bone morphogenetic proteins (BMPs), To understand the in vivo function of Smad5, we generated mice deficient in Smad5 using embryonic stem (ES) cell techno logy. Homozygous mutant embryos die between E9.5 and E11.5, and display var iable phenotypes. Morphological defects are first detected at E8.0 in the d eveloping amnion, gut and heart (the latter defect being similar to BMP-2 k nockout mice), At later stages, mutant embryos fail to undergo proper turni ng, have craniofacial and neural tube abnormalities, and are edematous. In addition, several extraembryonic lesions are observed. After E9.0, the yolk sacs of the mutants contain red blood cells but lack a well-organized vasc ulature, which is reminiscent of BMP-4. TGF-beta 1 and TGF-beta type II rec eptor knockout mice. In addition, the allantois of many Smad5 mutants is fu sed to the chorion, but is not well-elongated. A unique feature of the Smad 5 mutant embryos is that ectopic vasculogenesis and hematopoiesis is observ ed in the amnion, likely due to mislocation of allantois tissue. Despite th e expression of Smad5 from gastrulation onwards, and in contrast to knockou ts of Smad2 and Smad4, Smad5 only becomes essential later in extraembryonic and embryonic development.