TY - JOUR
T1 - Abdominal B (AbdB) Hoxa genes
T2 - Regulation in adult uterus by estrogen and progesterone and repression in Mullerian duct by the synthetic estrogen diethylstilbestrol (DES)
AU - Ma, Liang
AU - Benson, Gail V.
AU - Lim, Hyunjung
AU - Dey, Sudhansu K.
AU - Maas, Richard L.
N1 - Funding Information:
This work was supported by NICHD Grant HD35580 to R.L.M., by the Howard Hughes Medical Institute, and by NICHD Grants HD12304 and HD29968 to S.K.D. L.M. was supported by NIH NRSA (1F32 HD08264-01). G.V.B. was supported by an NIH training grant (T32 HD07390). H.L. is a Kansas Health Foundation Predoctoral Fellow. We gratefully acknowledge Dr. J. Innis (University of Michigan) for communicating results on Hypodactyly in advance of publication and Dr. William Chin (Harvard Medical School) and members of the Maas and Dey laboratories for critical comments on the manuscript.
PY - 1998/5/15
Y1 - 1998/5/15
N2 - Mice deficient for the Abdominal B (AbdB) Hox gene Hoxa-10 exhibit reduced fertility due to defects in implantation. During the peri- implantation period Hoxa-10 is sequentially expressed in the uterine epithelium and stroma. These observations, combined with the stringent regulation of uterine implantation by ovarian steroids, prompted us to test whether estrogen and progesterone directly regulate the expression of Hoxa- 10 and other AbdB Hoxa genes. Here we show that Hoxa-10 expression in the adult uterus is strongly activated by progesterone. This activation is blocked by the progesterone receptor antagonist RU486 and is independent of new protein synthesis. In addition, Hoxa-10 expression is repressed by estrogen in a protein synthesis-independent manner. Analysis of adjacent AbdB Hoxa genes reveals that Hoxa-9 and a-11 are also activated in a colinear fashion by progesterone but differentially regulated by estrogen. These results suggest that the regulation of AbdB Hox gene expression in the adult uterus by ovarian steroids is a property related to position within the cluster, mediated by the direct action of estrogen and progesterone receptors upon these genes. We next examined whether the embryonic expression of Hoxa10 is regulable by hormonal factors. Previous work has demonstrated that perinatal administration of the synthetic estrogen diethylstilbestrol (DES) to mice and humans produces uterine, cervical, and oviductal malformations. Certain of these phenotypes resemble those in Hoxa-10 knockout mice, suggesting that Hoxa-10 gene expression might be repressed by DES during reproductive tract morphogenesis. Exposure of the developing female reproductive tract to DES, either in vivo or in organ culture, represses the expression of Hoxa-10 in the Mullerian duct. Thus, these data not only establish a direct link between ovarian steroids and AbdB Hoxa gene expression in the adult uterus, but also provide a potential mechanism for the teratogenic effects of DES on the developing reproductive tract.
AB - Mice deficient for the Abdominal B (AbdB) Hox gene Hoxa-10 exhibit reduced fertility due to defects in implantation. During the peri- implantation period Hoxa-10 is sequentially expressed in the uterine epithelium and stroma. These observations, combined with the stringent regulation of uterine implantation by ovarian steroids, prompted us to test whether estrogen and progesterone directly regulate the expression of Hoxa- 10 and other AbdB Hoxa genes. Here we show that Hoxa-10 expression in the adult uterus is strongly activated by progesterone. This activation is blocked by the progesterone receptor antagonist RU486 and is independent of new protein synthesis. In addition, Hoxa-10 expression is repressed by estrogen in a protein synthesis-independent manner. Analysis of adjacent AbdB Hoxa genes reveals that Hoxa-9 and a-11 are also activated in a colinear fashion by progesterone but differentially regulated by estrogen. These results suggest that the regulation of AbdB Hox gene expression in the adult uterus by ovarian steroids is a property related to position within the cluster, mediated by the direct action of estrogen and progesterone receptors upon these genes. We next examined whether the embryonic expression of Hoxa10 is regulable by hormonal factors. Previous work has demonstrated that perinatal administration of the synthetic estrogen diethylstilbestrol (DES) to mice and humans produces uterine, cervical, and oviductal malformations. Certain of these phenotypes resemble those in Hoxa-10 knockout mice, suggesting that Hoxa-10 gene expression might be repressed by DES during reproductive tract morphogenesis. Exposure of the developing female reproductive tract to DES, either in vivo or in organ culture, represses the expression of Hoxa-10 in the Mullerian duct. Thus, these data not only establish a direct link between ovarian steroids and AbdB Hoxa gene expression in the adult uterus, but also provide a potential mechanism for the teratogenic effects of DES on the developing reproductive tract.
KW - AbdB Hox genes
KW - Diethylstilbestrol
KW - Estrogen
KW - Implantation
KW - Mullerian duct
KW - Progesterone
KW - Reproductive patterning
KW - Uterus
UR - http://www.scopus.com/inward/record.url?scp=0032523915&partnerID=8YFLogxK
U2 - 10.1006/dbio.1998.8907
DO - 10.1006/dbio.1998.8907
M3 - Article
C2 - 9630742
AN - SCOPUS:0032523915
VL - 197
SP - 141
EP - 154
JO - Developmental Biology
JF - Developmental Biology
SN - 0012-1606
IS - 2
ER -