Nature Genetics
21, 444 - 448 (1999)
doi:10.1038/7788
Embryonic retinoic acid synthesis is essential for early mouse post-implantation
developmentKaren Niederreither1, 3, Vemparala Subbarayan1, 2, 3, Pascal Dollé1, 3
& Pierre Chambon11
Institut de Génétique et de Biologie
Moléculaire et Cellulaire, CNRS/INSERM/ULP/Collège de France,
B.P. 163, 67404 Illkirch Cedex,
C.U. de Strasbourg, France. 2
Present address: MD Anderson Cancer Center, Department
of Clinical Cancer Prevention, Box 236, 1515 Holcombe Blvd,
Houston, Texas 77030, USA. 3
These authors contributed equally to this work.
Correspondence should be addressed to chambon@igbmc.u-strasbg.frA number of studies have suggested that the active derivative of vitamin
A, retinoic acid (RA), may be important for early development of mammalian
embryos1,
2. Severe vitamin A deprivation in rodents results
in maternal infertility3, precluding a thorough investigation
of the role of RA during embryogenesis. Here we show that production of RA
by the retinaldehyde dehydrogenase-2 (Raldh2) enzyme4,
5 is
required for mouse embryo survival and early morphogenesis. Raldh2 is an NAD-dependent
aldehyde dehydrogenase with high substrate specificity for retinaldehyde4,
5. Its pattern of expression during mouse development has suggested
that it may be responsible for embryonic RA synthesis4,
6. We
generated a targeted disruption of the mouse Raldh2 gene and found
that Raldh2−/− embryos, which die at midgestation
without undergoing axial rotation (body turning), exhibit shortening along
the anterioposterior axis and do not form limb buds. Their heart consists
of a single, medial, dilated cavity. Their frontonasal region is truncated
and their otocysts are severely reduced. These defects result from a block
in embryonic RA synthesis, as shown by the lack of activity of RA-responsive
transgenes, the altered expression of an RA-target homeobox gene and the near
full rescue of the mutant phenotype by maternal RA administration. Our data
establish that RA synthesized by the post-implantation mammalian embryo is
an essential developmental hormone whose lack leads to early embryo death.
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