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Hoxd10 Is Required Systemically for Secretory Activation in Lactation and Interacts Genetically with Hoxd9
Targeted disruption of the murine Hoxd10 gene (ΔHoxd10) leads to a high frequency of localized (gland-to-gland or regionally within a gland) lactation impairment in homozygous mutant mice as a single gene mutation. The effect of Hoxd10 disruption was enhanced by simultaneous disruption of Hoxd9 (ΔHo...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392944/ https://www.ncbi.nlm.nih.gov/pubmed/32705545 http://dx.doi.org/10.1007/s10911-020-09454-3 |
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author | Landua, John D. Moraes, Ricardo Carpenter, Ellen M. Lewis, Michael T. |
author_facet | Landua, John D. Moraes, Ricardo Carpenter, Ellen M. Lewis, Michael T. |
author_sort | Landua, John D. |
collection | PubMed |
description | Targeted disruption of the murine Hoxd10 gene (ΔHoxd10) leads to a high frequency of localized (gland-to-gland or regionally within a gland) lactation impairment in homozygous mutant mice as a single gene mutation. The effect of Hoxd10 disruption was enhanced by simultaneous disruption of Hoxd9 (ΔHoxd9/d10), a mutation shown previously to have no effect on mammary function as a single gene alteration. Mammary glands of homozygous ΔHoxd10 and ΔHoxd9/d10 females were indistinguishable from those of wild type littermate and age-matched control mice in late pregnancy. However, in lactation, 47% of homozygous ΔHoxd10 females, and 100% of homozygous ΔHoxd9/d10 females, showed localized or complete failure of two or more glands to undergo lactation-associated morphological changes and to secrete milk. Affected regions of ΔHoxd10 and ΔHoxd9/d10 mutants showed reduced prolactin receptor expression, reduced signal transducer and activator transcription protein 5 (STAT5) phosphorylation, reduced expression of downstream milk proteins, mislocalized glucose transporter 1 (GLUT1), increased STAT3 expression and phosphorylation, recruitment of leukocytes, altered cell cycle status, and increased apoptosis relative to unaffected regions and wild type control glands. Despite these local effects on alveolar function, transplantation results and hormone analysis indicate that Hoxd10 primarily has systemic functions that confer attenuated STAT5 phosphorylation on both wild type and ΔHoxd10 transplants when placed in ΔHoxd10 hosts, thereby exacerbating an underlying propensity for lactation failure in C57Bl/6 mice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10911-020-09454-3) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-7392944 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-73929442020-08-12 Hoxd10 Is Required Systemically for Secretory Activation in Lactation and Interacts Genetically with Hoxd9 Landua, John D. Moraes, Ricardo Carpenter, Ellen M. Lewis, Michael T. J Mammary Gland Biol Neoplasia Article Targeted disruption of the murine Hoxd10 gene (ΔHoxd10) leads to a high frequency of localized (gland-to-gland or regionally within a gland) lactation impairment in homozygous mutant mice as a single gene mutation. The effect of Hoxd10 disruption was enhanced by simultaneous disruption of Hoxd9 (ΔHoxd9/d10), a mutation shown previously to have no effect on mammary function as a single gene alteration. Mammary glands of homozygous ΔHoxd10 and ΔHoxd9/d10 females were indistinguishable from those of wild type littermate and age-matched control mice in late pregnancy. However, in lactation, 47% of homozygous ΔHoxd10 females, and 100% of homozygous ΔHoxd9/d10 females, showed localized or complete failure of two or more glands to undergo lactation-associated morphological changes and to secrete milk. Affected regions of ΔHoxd10 and ΔHoxd9/d10 mutants showed reduced prolactin receptor expression, reduced signal transducer and activator transcription protein 5 (STAT5) phosphorylation, reduced expression of downstream milk proteins, mislocalized glucose transporter 1 (GLUT1), increased STAT3 expression and phosphorylation, recruitment of leukocytes, altered cell cycle status, and increased apoptosis relative to unaffected regions and wild type control glands. Despite these local effects on alveolar function, transplantation results and hormone analysis indicate that Hoxd10 primarily has systemic functions that confer attenuated STAT5 phosphorylation on both wild type and ΔHoxd10 transplants when placed in ΔHoxd10 hosts, thereby exacerbating an underlying propensity for lactation failure in C57Bl/6 mice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10911-020-09454-3) contains supplementary material, which is available to authorized users. Springer US 2020-07-23 2020 /pmc/articles/PMC7392944/ /pubmed/32705545 http://dx.doi.org/10.1007/s10911-020-09454-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Landua, John D. Moraes, Ricardo Carpenter, Ellen M. Lewis, Michael T. Hoxd10 Is Required Systemically for Secretory Activation in Lactation and Interacts Genetically with Hoxd9 |
title | Hoxd10 Is Required Systemically for Secretory Activation in Lactation and Interacts Genetically with Hoxd9 |
title_full | Hoxd10 Is Required Systemically for Secretory Activation in Lactation and Interacts Genetically with Hoxd9 |
title_fullStr | Hoxd10 Is Required Systemically for Secretory Activation in Lactation and Interacts Genetically with Hoxd9 |
title_full_unstemmed | Hoxd10 Is Required Systemically for Secretory Activation in Lactation and Interacts Genetically with Hoxd9 |
title_short | Hoxd10 Is Required Systemically for Secretory Activation in Lactation and Interacts Genetically with Hoxd9 |
title_sort | hoxd10 is required systemically for secretory activation in lactation and interacts genetically with hoxd9 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392944/ https://www.ncbi.nlm.nih.gov/pubmed/32705545 http://dx.doi.org/10.1007/s10911-020-09454-3 |
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