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Single Enzyme Necessary For Normal Brain, Vertebrae, Urogenital Tract And Lower Body Development In Mammals

Date:
January 17, 2001
Source:
Cold Spring Harbor Laboratory
Summary:
Two independent research teams have discovered that a single enzyme is necessary for normal brain, vertebrae, urogenital tract and lower body embryological development in mammals. Dr. Hiroshi Hamada of Japan, Dr. Martin Petkovich of Canada, and their colleagues report in jointly published papers that the enzyme CPY26 metabolizes retinoic acid, an essential derivative of vitamin A. Retinoic acid (RA) regulates development by activating the expression of specific target genes throughout the embryo. The formation of an uneven distribution of RA along the central body axis of the developing embryo is essential for normal development.
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Two independent research teams have discovered that a single enzyme is necessary for normal brain, vertebrae, urogenital tract and lower body embryological development in mammals. Dr. Hiroshi Hamada of Japan, Dr. Martin Petkovich of Canada, and their colleagues report in jointly published papers that the enzyme CPY26 metabolizes retinoic acid, an essential derivative of vitamin A. Retinoic acid (RA) regulates development by activating the expression of specific target genes throughout the embryo. The formation of an uneven distribution of RA along the central body axis of the developing embryo is essential for normal development. By discovering that CPY26 degrades RA, and thereby establishes this uneven distribution of RA, scientists have determined that CPY26 plays a pivotal role in maintaining the fidelity of the mammalian embryo.

It has been known since the 1930s that vitamin A is necessary for normal embryological development. Since animal cells cannot make RA de novo, they must obtain it from dietary sources of vitamin A. Too little or too much vitamin A intake during pregnancy results in a host of characteristic morphological defects, including cranio-facial, cardiac, lung, genito-urinary and neurological abnormalities. Thus, there are stringent guidelines governing vitamin A consumption during pregnancy. The level of RA in the embryo is maintained by a delicate balance between RA synthesis and RA degredation. The effectiveness of RA as a developmental regulator depends on the precise control of its distribution.

In order to elucidate the developmental role of CPY26, Dr. Hamada, Dr. Petkovich and colleagues removed the gene Cpy26 from a srain of mice. Cpy26 mutant mouse embryos exhibited elevated levels of RA in those areas that normally express CPY26. This data established that CPY26 acts to metabolically degrade RA in vivo. The Cpy26 mutant mouse embryos were not viable; they exhibited major defects including spina bifida, truncation of the posterior body, kidney, brain and vertebrae abnormalities. The most severe developmental defect resulting from the loss of CPY26 activity was complete hindlimb fusion, resulting in a ‘mermaid tail’. Since the CPY26 knock-out mice phenotypes closely resembled those resulting from excess RA, this suggested further that CPY26 functions normally to maintain specific areas of the developing embryo in an RA depleted state.

Dr. Hamada, Dr. Petkovich and colleagues have demonstrated that CPY26 acts to protect the developing mammalian embryo from the deleterious effects of excessive RA activity. The discovery that CPY26 functions to restrict the field of RA signaling represents a significant advance in our understanding of the role and pattern of retinoic acid activity in the developing embryo. Further work to delineate the pathway of CPY26 action will lend insight into the molecular mechanisms of RA-associated congenital defects like spina bifida, fetal vitamin A deficiency syndrome and caudal regression syndrome.


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The above story is based on materials provided by Cold Spring Harbor Laboratory. Note: Materials may be edited for content and length.


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Cold Spring Harbor Laboratory. "Single Enzyme Necessary For Normal Brain, Vertebrae, Urogenital Tract And Lower Body Development In Mammals." ScienceDaily. ScienceDaily, 17 January 2001. <www.sciencedaily.com/releases/2001/01/010116080119.htm>.
Cold Spring Harbor Laboratory. (2001, January 17). Single Enzyme Necessary For Normal Brain, Vertebrae, Urogenital Tract And Lower Body Development In Mammals. ScienceDaily. Retrieved April 28, 2015 from www.sciencedaily.com/releases/2001/01/010116080119.htm
Cold Spring Harbor Laboratory. "Single Enzyme Necessary For Normal Brain, Vertebrae, Urogenital Tract And Lower Body Development In Mammals." ScienceDaily. www.sciencedaily.com/releases/2001/01/010116080119.htm (accessed April 28, 2015).

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