Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects
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Updated: Oct 24, 2026
A Reverse Genetic Approach to Test Functional Redundancy During Embryogenesis
Published on: August 11, 2010
H Chang1, D Huylebroeck, K Verschueren
1Departments of Pathology, Cell Biology and Molecular and Human Genetics, and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA. mmatzuk@bcm.tmc.edu
Abstract:
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 technology. Homozygous mutant embryos die between E9.5 and E11.5, and display variable phenotypes. Morphological defects are first detected at E8.0 in the developing amnion, gut and heart (the latter defect being similar to BMP-2 knockout mice). At later stages, mutant embryos fail to undergo proper turning, 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 vasculature, which is reminiscent of BMP-4, TGF-beta1 and TGF-beta type II receptor knockout mice. In addition, the allantois of many Smad5 mutants is fused to the chorion, but is not well-elongated. A unique feature of the Smad5 mutant embryos is that ectopic vasculogenesis and hematopoiesis is observed in the amnion, likely due to mislocation of allantois tissue. Despite the expression of Smad5 from gastrulation onwards, and in contrast to knockouts of Smad2 and Smad4, Smad5 only becomes essential later in extraembryonic and embryonic development.
Insights
Smad5 is crucial for embryonic development, mediating bone morphogenetic protein (BMP) signals. Smad5-deficient mice exhibit severe developmental defects, including vascular and heart abnormalities, leading to embryonic lethality.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Smad5 acts as a downstream mediator for bone morphogenetic proteins (BMPs).
- Understanding the in vivo function of Smad5 is essential for comprehending BMP signaling pathways.
- Previous studies have implicated BMPs in various developmental processes.
Purpose of the Study:
- To investigate the in vivo function of Smad5 during embryonic development.
- To characterize the phenotypic consequences of Smad5 deficiency in mice.
Main Methods:
- Generation of Smad5-deficient mice using embryonic stem (ES) cell technology.
- Detailed morphological and developmental analysis of homozygous mutant embryos.
Main Results:
- Smad5-deficient embryos exhibit embryonic lethality between embryonic day 9.5 and 11.5.
- Mutant embryos display variable phenotypes, including defects in amnion, gut, heart, craniofacial structures, and neural tube.
- Extraembryonic defects include abnormal yolk sac vasculature and allantois development.
- Ectopic vasculogenesis and hematopoiesis are observed in the amnion of Smad5 mutants.
Conclusions:
- Smad5 is essential for proper embryonic and extraembryonic development.
- Smad5 plays a critical role in vasculogenesis and hematopoiesis.
- Unlike Smad2 and Smad4, Smad5 function becomes essential later in development.
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