Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse
ABSTRACT Uterine receptivity implies a dialogue between the hormonally primed maternal endometrium and the free‐floating blastocyst. Endometrial stromal cells proliferate, avert apoptosis, and undergo decidualization in preparation for implantation; however, the molecular mechanisms that underlie di...
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| creator | Afshar, Yalda Jeong, Jae‐Wook Roqueiro, Damian DeMayo, Franco Lydon, John Radtke, Freddy Radnor, Rachel Miele, Lucio Fazleabas, Asgerally |
| description | ABSTRACT
Uterine receptivity implies a dialogue between the hormonally primed maternal endometrium and the free‐floating blastocyst. Endometrial stromal cells proliferate, avert apoptosis, and undergo decidualization in preparation for implantation; however, the molecular mechanisms that underlie differentiation into the decidual phenotype remain largely undefined. The Notch family of transmembrane receptors transduce extracellular signals responsible for cell survival, cell‐to‐cell communication, and differentiation, all fundamental processes for decidualization and pregnancy. Using a murine artificial decidualization model, pharmacological inhibition of Notch signaling by γ‐secretase inhibition resulted in a significantly decreased deciduoma. Furthermore, a progesterone receptor (PR)‐Cre Notch1 bigenic (Notch1d/d) confirmed a Notch1‐dependent hypomorphic decidual phenotype. Microarray and pathway analysis, following Notch1 ablation, demonstrated significantly altered signaling repertoire. Concomitantly, hierarchical clustering demonstrated Notch1‐dependent differences in gene expression. Uteri deprived of Notch1 signaling demonstrated decreased cellular proliferation; namely, reduced proliferation‐specific antigen, Ki67, altered p21, cdk6, and cyclinD activity and an increased apoptotic‐profile, cleaved caspase‐3, Bad, and attenuated Bcl2. The results demonstrate that the preimplantation uterus relies on Notch signaling to inhibit apoptosis of stromal fibroblasts and regulate cell cycle progression, which together promotes successful decidualization. In summary, Notch1 signaling modulates multiple signaling mechanisms crucial for decidualization and these studies provide additional perspectives to the coordination of multiple signaling modalities required during decidualization.—Afshar, Y., Jeong, J.‐W., Roqueiro, D., DeMayo, F., Lydon, J., Radtke, F., Radnor, R., Miele, L., Fazleabas, A. Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse. FASEB J. 26, 282–294 (2012). www.fasebj.org |
| doi_str_mv | 10.1096/fj.11-184663 |
| format | Article |
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Uterine receptivity implies a dialogue between the hormonally primed maternal endometrium and the free‐floating blastocyst. Endometrial stromal cells proliferate, avert apoptosis, and undergo decidualization in preparation for implantation; however, the molecular mechanisms that underlie differentiation into the decidual phenotype remain largely undefined. The Notch family of transmembrane receptors transduce extracellular signals responsible for cell survival, cell‐to‐cell communication, and differentiation, all fundamental processes for decidualization and pregnancy. Using a murine artificial decidualization model, pharmacological inhibition of Notch signaling by γ‐secretase inhibition resulted in a significantly decreased deciduoma. Furthermore, a progesterone receptor (PR)‐Cre Notch1 bigenic (Notch1d/d) confirmed a Notch1‐dependent hypomorphic decidual phenotype. Microarray and pathway analysis, following Notch1 ablation, demonstrated significantly altered signaling repertoire. Concomitantly, hierarchical clustering demonstrated Notch1‐dependent differences in gene expression. Uteri deprived of Notch1 signaling demonstrated decreased cellular proliferation; namely, reduced proliferation‐specific antigen, Ki67, altered p21, cdk6, and cyclinD activity and an increased apoptotic‐profile, cleaved caspase‐3, Bad, and attenuated Bcl2. The results demonstrate that the preimplantation uterus relies on Notch signaling to inhibit apoptosis of stromal fibroblasts and regulate cell cycle progression, which together promotes successful decidualization. In summary, Notch1 signaling modulates multiple signaling mechanisms crucial for decidualization and these studies provide additional perspectives to the coordination of multiple signaling modalities required during decidualization.—Afshar, Y., Jeong, J.‐W., Roqueiro, D., DeMayo, F., Lydon, J., Radtke, F., Radnor, R., Miele, L., Fazleabas, A. Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse. FASEB J. 26, 282–294 (2012). www.fasebj.org</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.11-184663</identifier><identifier>PMID: 21990372</identifier><language>eng</language><publisher>United States: Federation of American Societies for Experimental Biology</publisher><subject>Animals ; Apoptosis - physiology ; Cell Communication - physiology ; Cell Differentiation - physiology ; Cell Division - physiology ; Cytoskeleton - metabolism ; Decidua - cytology ; Decidua - physiology ; Embryo Implantation - physiology ; endometrium ; Female ; implantation ; Key Words ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Oligonucleotide Array Sequence Analysis ; Ovariectomy ; Pregnancy ; Pregnancy, Animal - physiology ; Receptor, Notch1 - genetics ; Receptor, Notch1 - metabolism ; reproduction ; Research Communications ; Signal Transduction - physiology ; Stromal Cells - cytology ; Stromal Cells - metabolism</subject><ispartof>The FASEB journal, 2012-01, Vol.26 (1), p.282-294</ispartof><rights>FASEB</rights><rights>FASEB 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4983-89e8470379a906335882d477d4d1857cd55445570032ce8bc2ac43d06bf3fe0a3</citedby><cites>FETCH-LOGICAL-c4983-89e8470379a906335882d477d4d1857cd55445570032ce8bc2ac43d06bf3fe0a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1096%2Ffj.11-184663$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1096%2Ffj.11-184663$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21990372$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Afshar, Yalda</creatorcontrib><creatorcontrib>Jeong, Jae‐Wook</creatorcontrib><creatorcontrib>Roqueiro, Damian</creatorcontrib><creatorcontrib>DeMayo, Franco</creatorcontrib><creatorcontrib>Lydon, John</creatorcontrib><creatorcontrib>Radtke, Freddy</creatorcontrib><creatorcontrib>Radnor, Rachel</creatorcontrib><creatorcontrib>Miele, Lucio</creatorcontrib><creatorcontrib>Fazleabas, Asgerally</creatorcontrib><title>Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>ABSTRACT
Uterine receptivity implies a dialogue between the hormonally primed maternal endometrium and the free‐floating blastocyst. Endometrial stromal cells proliferate, avert apoptosis, and undergo decidualization in preparation for implantation; however, the molecular mechanisms that underlie differentiation into the decidual phenotype remain largely undefined. The Notch family of transmembrane receptors transduce extracellular signals responsible for cell survival, cell‐to‐cell communication, and differentiation, all fundamental processes for decidualization and pregnancy. Using a murine artificial decidualization model, pharmacological inhibition of Notch signaling by γ‐secretase inhibition resulted in a significantly decreased deciduoma. Furthermore, a progesterone receptor (PR)‐Cre Notch1 bigenic (Notch1d/d) confirmed a Notch1‐dependent hypomorphic decidual phenotype. Microarray and pathway analysis, following Notch1 ablation, demonstrated significantly altered signaling repertoire. Concomitantly, hierarchical clustering demonstrated Notch1‐dependent differences in gene expression. Uteri deprived of Notch1 signaling demonstrated decreased cellular proliferation; namely, reduced proliferation‐specific antigen, Ki67, altered p21, cdk6, and cyclinD activity and an increased apoptotic‐profile, cleaved caspase‐3, Bad, and attenuated Bcl2. The results demonstrate that the preimplantation uterus relies on Notch signaling to inhibit apoptosis of stromal fibroblasts and regulate cell cycle progression, which together promotes successful decidualization. In summary, Notch1 signaling modulates multiple signaling mechanisms crucial for decidualization and these studies provide additional perspectives to the coordination of multiple signaling modalities required during decidualization.—Afshar, Y., Jeong, J.‐W., Roqueiro, D., DeMayo, F., Lydon, J., Radtke, F., Radnor, R., Miele, L., Fazleabas, A. Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse. FASEB J. 26, 282–294 (2012). www.fasebj.org</description><subject>Animals</subject><subject>Apoptosis - physiology</subject><subject>Cell Communication - physiology</subject><subject>Cell Differentiation - physiology</subject><subject>Cell Division - physiology</subject><subject>Cytoskeleton - metabolism</subject><subject>Decidua - cytology</subject><subject>Decidua - physiology</subject><subject>Embryo Implantation - physiology</subject><subject>endometrium</subject><subject>Female</subject><subject>implantation</subject><subject>Key Words</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Ovariectomy</subject><subject>Pregnancy</subject><subject>Pregnancy, Animal - physiology</subject><subject>Receptor, Notch1 - genetics</subject><subject>Receptor, Notch1 - metabolism</subject><subject>reproduction</subject><subject>Research Communications</subject><subject>Signal Transduction - physiology</subject><subject>Stromal Cells - cytology</subject><subject>Stromal Cells - metabolism</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1v1DAQxS0Eokvhxhn5xoWU8UcS-4JEK5YPVXAAzpbXnrBeJfFiO6Dy1-MqSwUXTiPN--nNGz1CnjK4YKC7l8PhgrGGKdl14h7ZsFZA06kO7pMNKM2bulZn5FHOBwBgwLqH5IwzrUH0fEPCx1jcntEJfbAFM10KpjAjzSXFyY7Uh2HAhHOpcogztbOnIVOXQgmu6kNM1MXpOGJB6tEFv9gx_FrhMNOyRzrFJeNj8mCwY8Ynp3lOvm7ffLl611x_evv-6vV146RWolEalexrOG01dEK0SnEv-95Lz1TbO9-2UrZtDyC4Q7Vz3DopPHS7QQwIVpyTV6vvcdnVr1yNnuxojilMNt2YaIP5V5nD3nyLP4zgLXAJ1eD5ySDF7wvmYqaQHY6jnbE-YjSTXGvJb8kXK-lSzDnhcHeFgbktxwwHw5hZy6n4s7-T3cF_2qiAWoGfYcSb_5qZ7edLvv3A2Mn7N9psnOw</recordid><startdate>201201</startdate><enddate>201201</enddate><creator>Afshar, Yalda</creator><creator>Jeong, Jae‐Wook</creator><creator>Roqueiro, Damian</creator><creator>DeMayo, Franco</creator><creator>Lydon, John</creator><creator>Radtke, Freddy</creator><creator>Radnor, Rachel</creator><creator>Miele, Lucio</creator><creator>Fazleabas, Asgerally</creator><general>Federation of American Societies for Experimental Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201201</creationdate><title>Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse</title><author>Afshar, Yalda ; Jeong, Jae‐Wook ; Roqueiro, Damian ; DeMayo, Franco ; Lydon, John ; Radtke, Freddy ; Radnor, Rachel ; Miele, Lucio ; Fazleabas, Asgerally</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4983-89e8470379a906335882d477d4d1857cd55445570032ce8bc2ac43d06bf3fe0a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Apoptosis - physiology</topic><topic>Cell Communication - physiology</topic><topic>Cell Differentiation - physiology</topic><topic>Cell Division - physiology</topic><topic>Cytoskeleton - metabolism</topic><topic>Decidua - cytology</topic><topic>Decidua - physiology</topic><topic>Embryo Implantation - physiology</topic><topic>endometrium</topic><topic>Female</topic><topic>implantation</topic><topic>Key Words</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>Ovariectomy</topic><topic>Pregnancy</topic><topic>Pregnancy, Animal - physiology</topic><topic>Receptor, Notch1 - genetics</topic><topic>Receptor, Notch1 - metabolism</topic><topic>reproduction</topic><topic>Research Communications</topic><topic>Signal Transduction - physiology</topic><topic>Stromal Cells - cytology</topic><topic>Stromal Cells - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Afshar, Yalda</creatorcontrib><creatorcontrib>Jeong, Jae‐Wook</creatorcontrib><creatorcontrib>Roqueiro, Damian</creatorcontrib><creatorcontrib>DeMayo, Franco</creatorcontrib><creatorcontrib>Lydon, John</creatorcontrib><creatorcontrib>Radtke, Freddy</creatorcontrib><creatorcontrib>Radnor, Rachel</creatorcontrib><creatorcontrib>Miele, Lucio</creatorcontrib><creatorcontrib>Fazleabas, Asgerally</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Afshar, Yalda</au><au>Jeong, Jae‐Wook</au><au>Roqueiro, Damian</au><au>DeMayo, Franco</au><au>Lydon, John</au><au>Radtke, Freddy</au><au>Radnor, Rachel</au><au>Miele, Lucio</au><au>Fazleabas, Asgerally</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2012-01</date><risdate>2012</risdate><volume>26</volume><issue>1</issue><spage>282</spage><epage>294</epage><pages>282-294</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><abstract>ABSTRACT
Uterine receptivity implies a dialogue between the hormonally primed maternal endometrium and the free‐floating blastocyst. Endometrial stromal cells proliferate, avert apoptosis, and undergo decidualization in preparation for implantation; however, the molecular mechanisms that underlie differentiation into the decidual phenotype remain largely undefined. The Notch family of transmembrane receptors transduce extracellular signals responsible for cell survival, cell‐to‐cell communication, and differentiation, all fundamental processes for decidualization and pregnancy. Using a murine artificial decidualization model, pharmacological inhibition of Notch signaling by γ‐secretase inhibition resulted in a significantly decreased deciduoma. Furthermore, a progesterone receptor (PR)‐Cre Notch1 bigenic (Notch1d/d) confirmed a Notch1‐dependent hypomorphic decidual phenotype. Microarray and pathway analysis, following Notch1 ablation, demonstrated significantly altered signaling repertoire. Concomitantly, hierarchical clustering demonstrated Notch1‐dependent differences in gene expression. Uteri deprived of Notch1 signaling demonstrated decreased cellular proliferation; namely, reduced proliferation‐specific antigen, Ki67, altered p21, cdk6, and cyclinD activity and an increased apoptotic‐profile, cleaved caspase‐3, Bad, and attenuated Bcl2. The results demonstrate that the preimplantation uterus relies on Notch signaling to inhibit apoptosis of stromal fibroblasts and regulate cell cycle progression, which together promotes successful decidualization. In summary, Notch1 signaling modulates multiple signaling mechanisms crucial for decidualization and these studies provide additional perspectives to the coordination of multiple signaling modalities required during decidualization.—Afshar, Y., Jeong, J.‐W., Roqueiro, D., DeMayo, F., Lydon, J., Radtke, F., Radnor, R., Miele, L., Fazleabas, A. Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse. FASEB J. 26, 282–294 (2012). www.fasebj.org</abstract><cop>United States</cop><pub>Federation of American Societies for Experimental Biology</pub><pmid>21990372</pmid><doi>10.1096/fj.11-184663</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis - physiology Cell Communication - physiology Cell Differentiation - physiology Cell Division - physiology Cytoskeleton - metabolism Decidua - cytology Decidua - physiology Embryo Implantation - physiology endometrium Female implantation Key Words Mice Mice, Inbred C57BL Mice, Knockout Oligonucleotide Array Sequence Analysis Ovariectomy Pregnancy Pregnancy, Animal - physiology Receptor, Notch1 - genetics Receptor, Notch1 - metabolism reproduction Research Communications Signal Transduction - physiology Stromal Cells - cytology Stromal Cells - metabolism |
| title | Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse |
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