The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2 - PubMed (original) (raw)

The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2

Quanxi Li et al. Science. 2011.

Abstract

During pregnancy, progesterone inhibits the growth-promoting actions of estrogen in the uterus. However, the mechanism for this is not clear. The attenuation of estrogen-mediated proliferation of the uterine epithelium by progesterone is a prerequisite for successful implantation. Our study reveals that progesterone-induced expression of the basic helix-loop-helix transcription factor Hand2 in the uterine stroma suppresses the production of several fibroblast growth factors (FGFs) that act as paracrine mediators of mitogenic effects of estrogen on the epithelium. In mouse uteri lacking Hand2, continued induction of these FGFs in the stroma maintains epithelial proliferation and stimulates estrogen-induced pathways, resulting in impaired implantation. Thus, Hand2 is a critical regulator of the uterine stromal-epithelial communication that directs proper steroid regulation conducive for the establishment of pregnancy.

PubMed Disclaimer

Figures

Figure 1

Figure 1

P-regulated expression of Hand2 in the uterus is critical for implantation. (A) IHC of Hand2 protein in the uterine sections of ovariectomized WT mice treated with vehicle (a) or P (b) and PR-null mice treated with P (c). Panel d represents sections treated with non-immune IgG. (B) Uterine sections obtained from mice on days 2 to 4 of pregnancy were subjected to IHC using Hand2 antibody. Magnification 20X. (C) H and E staining of uterine sections obtained from Hand2f/f (a, b) and Hand2d/d (c, d) mice on day 5 (n=6) of pregnancy. b and d represent magnified images of a and c, respectively. Solid and dotted arrows point to embryo and luminal epithelium. L and S represent luminal epithelium and stroma, respectively.

Figure 1

Figure 1

P-regulated expression of Hand2 in the uterus is critical for implantation. (A) IHC of Hand2 protein in the uterine sections of ovariectomized WT mice treated with vehicle (a) or P (b) and PR-null mice treated with P (c). Panel d represents sections treated with non-immune IgG. (B) Uterine sections obtained from mice on days 2 to 4 of pregnancy were subjected to IHC using Hand2 antibody. Magnification 20X. (C) H and E staining of uterine sections obtained from Hand2f/f (a, b) and Hand2d/d (c, d) mice on day 5 (n=6) of pregnancy. b and d represent magnified images of a and c, respectively. Solid and dotted arrows point to embryo and luminal epithelium. L and S represent luminal epithelium and stroma, respectively.

Figure 1

Figure 1

P-regulated expression of Hand2 in the uterus is critical for implantation. (A) IHC of Hand2 protein in the uterine sections of ovariectomized WT mice treated with vehicle (a) or P (b) and PR-null mice treated with P (c). Panel d represents sections treated with non-immune IgG. (B) Uterine sections obtained from mice on days 2 to 4 of pregnancy were subjected to IHC using Hand2 antibody. Magnification 20X. (C) H and E staining of uterine sections obtained from Hand2f/f (a, b) and Hand2d/d (c, d) mice on day 5 (n=6) of pregnancy. b and d represent magnified images of a and c, respectively. Solid and dotted arrows point to embryo and luminal epithelium. L and S represent luminal epithelium and stroma, respectively.

Figure 2

Figure 2

Enhanced ERα activity and proliferation in the luminal epithelium of Hand2d/d uteri. (A) Real-time PCR was performed to monitor the expression of Muc1 and Ltf in the uteri of day 4 pregnant Hand2f/f and Hand2d/d mice, *P<0.001. (B) IHC of Ki67 in Hand2f/f (a) and Hand2d/d (b) uteri on day 4 of pregnancy, 20X. Panel c shows uterine sections from Hand2d/d mice treated with non-immune IgG, 40X. (C) IHC of Ki67 in the uterine sections of ovariectomized Hand2f/f and Hand2d/d mice treated with E for one day (a and b), P for three days (c and d) or two days of P treatment followed by P and E (e and f).

Figure 2

Figure 2

Enhanced ERα activity and proliferation in the luminal epithelium of Hand2d/d uteri. (A) Real-time PCR was performed to monitor the expression of Muc1 and Ltf in the uteri of day 4 pregnant Hand2f/f and Hand2d/d mice, *P<0.001. (B) IHC of Ki67 in Hand2f/f (a) and Hand2d/d (b) uteri on day 4 of pregnancy, 20X. Panel c shows uterine sections from Hand2d/d mice treated with non-immune IgG, 40X. (C) IHC of Ki67 in the uterine sections of ovariectomized Hand2f/f and Hand2d/d mice treated with E for one day (a and b), P for three days (c and d) or two days of P treatment followed by P and E (e and f).

Figure 2

Figure 2

Enhanced ERα activity and proliferation in the luminal epithelium of Hand2d/d uteri. (A) Real-time PCR was performed to monitor the expression of Muc1 and Ltf in the uteri of day 4 pregnant Hand2f/f and Hand2d/d mice, *P<0.001. (B) IHC of Ki67 in Hand2f/f (a) and Hand2d/d (b) uteri on day 4 of pregnancy, 20X. Panel c shows uterine sections from Hand2d/d mice treated with non-immune IgG, 40X. (C) IHC of Ki67 in the uterine sections of ovariectomized Hand2f/f and Hand2d/d mice treated with E for one day (a and b), P for three days (c and d) or two days of P treatment followed by P and E (e and f).

Figure 3

Figure 3

Enhanced FGFR signaling in the luminal epithelium of Hand2d/d uteri. (A) Relative level of expression of Fgf family of growth factors in the uterine stroma of Hand2f/f and Hand2d/d mice on day 4 of pregnancy, *P<0.001. The levels of p-FRS2 (B) and p-ERK1/2 (C) were examined in the uterine sections (n=3) of both genotypes by IHC. a & b represent uterine sections obtained from day 4 pregnant mice. c & d indicate uterine sections from ovariectomized mice treated with two days of P followed by P and E.

Figure 3

Figure 3

Enhanced FGFR signaling in the luminal epithelium of Hand2d/d uteri. (A) Relative level of expression of Fgf family of growth factors in the uterine stroma of Hand2f/f and Hand2d/d mice on day 4 of pregnancy, *P<0.001. The levels of p-FRS2 (B) and p-ERK1/2 (C) were examined in the uterine sections (n=3) of both genotypes by IHC. a & b represent uterine sections obtained from day 4 pregnant mice. c & d indicate uterine sections from ovariectomized mice treated with two days of P followed by P and E.

Figure 3

Figure 3

Enhanced FGFR signaling in the luminal epithelium of Hand2d/d uteri. (A) Relative level of expression of Fgf family of growth factors in the uterine stroma of Hand2f/f and Hand2d/d mice on day 4 of pregnancy, *P<0.001. The levels of p-FRS2 (B) and p-ERK1/2 (C) were examined in the uterine sections (n=3) of both genotypes by IHC. a & b represent uterine sections obtained from day 4 pregnant mice. c & d indicate uterine sections from ovariectomized mice treated with two days of P followed by P and E.

Figure 4

Figure 4

The inhibitor PD173074 (A) or PD184352 (B) was administered to one uterine horn of Hand2_d/d_ mice on day 3 of pregnancy (n=5). The other horn served as vehicle-treated control. Uterine horns were collected on day 4 morning and sections were subjected to IHC to detect p-FRS2, p-ERK1/2, and Ki67 (C) IHC of pERα and Muc-1 in uterine sections of Hand2_d/d_ mice treated with PD173074 or PD184352.

Figure 4

Figure 4

The inhibitor PD173074 (A) or PD184352 (B) was administered to one uterine horn of Hand2_d/d_ mice on day 3 of pregnancy (n=5). The other horn served as vehicle-treated control. Uterine horns were collected on day 4 morning and sections were subjected to IHC to detect p-FRS2, p-ERK1/2, and Ki67 (C) IHC of pERα and Muc-1 in uterine sections of Hand2_d/d_ mice treated with PD173074 or PD184352.

Figure 4

Figure 4

The inhibitor PD173074 (A) or PD184352 (B) was administered to one uterine horn of Hand2_d/d_ mice on day 3 of pregnancy (n=5). The other horn served as vehicle-treated control. Uterine horns were collected on day 4 morning and sections were subjected to IHC to detect p-FRS2, p-ERK1/2, and Ki67 (C) IHC of pERα and Muc-1 in uterine sections of Hand2_d/d_ mice treated with PD173074 or PD184352.

Comment in

Similar articles

Cited by

References

    1. Finn CA, Martin L. J Reprod Fert. 1974;39:195. - PubMed
    1. Carson DD, et al. Dev Biol. 2000;223:217. - PubMed
    1. Ramathal CY, et al. Semin Reprod Med. 2010;28:17. - PMC - PubMed
    1. Martin L, Das RM. J Endocrinol. 1973;57:549. - PubMed
    1. Bagchi IC, et al. Front Biosci. 2003;8:s852. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources