Hoxa-10 deficiency alters region-specific gene expression and perturbs differentiation of natural killer cells during decidualization.
Uterine decidualization, a key event for successful implantation, is critically controlled by stromal cell proliferation and differentiation. One hallmark event of decidualization is the acquisition of stromal cell polyploidy through terminal differentiation at the anti-mesometrial pole of the implantation site. Hoxa-10, a developmentally regulated homeobox transcription factor, is highly expressed in decidualizing stromal cells, and targeted deletion of Hoxa-10 in mice shows severe decidualization defects, primarily due to reduced stromal cell responsiveness to progesterone. However, the underlying molecular mechanism by which Hoxa-10 regulates this process remains largely unknown. Here, we show that Hoxa-10 deficiency confers diminished core cell cycle activity during stromal cell proliferation without disturbing polyploidy, suggesting that these events depend on local regulators that impact cell cycle machinery. To further address this question, we compared global gene expression profiles in uteri of wild-type and Hoxa-10(-/-) mice after inducing decidualization. Our studies show two major aspects of decidualization downstream of Hoxa-10. First, Hoxa-10 deficiency results in the aberrant region-specific expression of cyclin-dependent kinase-4 (cdk4) and -6 (cdk6), growth differentiation factor 10 (Gdf10), hepatocyte growth factor (Hgf) and Snail2. Second, Hoxa-10 deficiency compromises natural killer (NK) cell differentiation without altering trafficking of NK precursor cells during decidualization. Collectively, the results provide evidence that Hoxa-10 influences a host of genes and cell functions necessary for propagating normal decidual development during the post-implantation period.
Rahman
Mohammad A
MA
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Li
Meiling
M
Li
Ping
P
Wang
Haibin
H
Dey
Sudhansu K
SK
Das
Sanjoy K
SK
D000818:Animals; D055398:Bone Morphogenetic Protein 3; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D003656:Decidua / Q000502:physiology*; D010064:Embryo Implantation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055413:Growth Differentiation Factor 10; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011123:Polyploidy; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014599:Uterus / Q000502:physiology
D055398:Bone Morphogenetic Protein 3; D019485:Bone Morphogenetic Proteins; C525784:Gdf10 protein, mouse; D055413:Growth Differentiation Factor 10; D018398:Homeodomain Proteins; C094041:Hoxa11 protein, mouse; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6