Dysregulation of uterine signaling pathways in progesterone receptor-cre knockout of dicer

Shannon Hawkins, Claudia V. Andreu-Vieyra, Tae Hoon Kim, Jae Wook Jeong, Myles C. Hodgson, Ruihong Chen, Chad J. Creighton, John P. Lydon, Preethi H. Gunaratne, Francesco J. DeMayo, Martin M. Matzuk

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Epithelial-stromal interactions in the uterus are required for normal uterine functions such as pregnancy, and multiple signaling pathways are essential for this process. Although Dicer and microRNA (miRNA) have been implicated in several reproductive processes, the specific roles of Dicer and miRNA in uterine development are not known. To address the roles of miRNA in the regulation of key uterine pathways, we generated a conditional knockout of Dicer in the postnatal uterine epithelium and stroma using progesterone receptor-Cre. These Dicer conditional knockout females are sterile with small uteri, which demonstrate significant defects, including absence of glandular epithelium and enhanced stromal apoptosis, beginning at approximately postnatal d 15, with coincident expression of Cre and deletion of Dicer. Specific miRNA (miR-181c, -200b, -101, let-7d) were down-regulated and corresponding predicted proapoptotic target genes (Bcl2l11, Aldh1a3) were up-regulated, reflecting the apoptotic phenomenon. Although these mice had normal serum hormone levels, critical uterine signaling pathways, including progesterone-responsive genes, Indian hedgehog signaling, and the Wnt/β-catenin canonical pathway, were dysregulated at the mRNA level. Importantly, uterine stromal cell proliferation in response to progesterone was absent, whereas uterine epithelial cell proliferation in response to estradiol was maintained in adult uteri. These data implicate Dicer and appropriate miRNA expression as essential players in the regulation of multiple uterine signaling pathways required for uterine development and appropriate function.

Original languageEnglish (US)
Pages (from-to)1552-1566
Number of pages15
JournalMolecular Endocrinology
Volume26
Issue number9
DOIs
StatePublished - Sep 2012
Externally publishedYes

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Progesterone Receptors
MicroRNAs
Uterus
Progesterone
Epithelium
Cell Proliferation
Catenins
Multiple Pregnancy
Wnt Signaling Pathway
Hedgehogs
Stromal Cells
Genes
Estradiol
Epithelial Cells
Hormones
Apoptosis
Messenger RNA
Serum

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Hawkins, S., Andreu-Vieyra, C. V., Kim, T. H., Jeong, J. W., Hodgson, M. C., Chen, R., ... Matzuk, M. M. (2012). Dysregulation of uterine signaling pathways in progesterone receptor-cre knockout of dicer. Molecular Endocrinology, 26(9), 1552-1566. https://doi.org/10.1210/me.2012-1042

Dysregulation of uterine signaling pathways in progesterone receptor-cre knockout of dicer. / Hawkins, Shannon; Andreu-Vieyra, Claudia V.; Kim, Tae Hoon; Jeong, Jae Wook; Hodgson, Myles C.; Chen, Ruihong; Creighton, Chad J.; Lydon, John P.; Gunaratne, Preethi H.; DeMayo, Francesco J.; Matzuk, Martin M.

In: Molecular Endocrinology, Vol. 26, No. 9, 09.2012, p. 1552-1566.

Research output: Contribution to journalArticle

Hawkins, S, Andreu-Vieyra, CV, Kim, TH, Jeong, JW, Hodgson, MC, Chen, R, Creighton, CJ, Lydon, JP, Gunaratne, PH, DeMayo, FJ & Matzuk, MM 2012, 'Dysregulation of uterine signaling pathways in progesterone receptor-cre knockout of dicer', Molecular Endocrinology, vol. 26, no. 9, pp. 1552-1566. https://doi.org/10.1210/me.2012-1042
Hawkins, Shannon ; Andreu-Vieyra, Claudia V. ; Kim, Tae Hoon ; Jeong, Jae Wook ; Hodgson, Myles C. ; Chen, Ruihong ; Creighton, Chad J. ; Lydon, John P. ; Gunaratne, Preethi H. ; DeMayo, Francesco J. ; Matzuk, Martin M. / Dysregulation of uterine signaling pathways in progesterone receptor-cre knockout of dicer. In: Molecular Endocrinology. 2012 ; Vol. 26, No. 9. pp. 1552-1566.
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