FOXA1 deletion in luminal epithelium causes prostatic hyperplasia and alteration of differentiated phenotype.
The forkhead box (Fox) superfamily of transcription factors has essential roles in organogenesis and tissue differentiation. Foxa1 and Foxa2 are expressed during prostate budding and ductal morphogenesis, whereas Foxa1 expression is retained in adult prostate epithelium. Previous characterization of prostatic tissue rescued from embryonic Foxa1 knockout mice revealed Foxa1 to be essential for ductal morphogenesis and epithelial maturation. However, it is unknown whether Foxa1 is required to maintain the differentiated status in adult prostate epithelium. Here, we employed the PBCre4 transgenic system and determined the impact of prostate-specific Foxa1 deletion in adult murine epithelium. PBCre4/Foxa1(loxp/loxp) mouse prostates showed progressive florid hyperplasia with extensive cribriform patterning, with the anterior prostate being most affected. Immunohistochemistry studies show mosaic Foxa1 KO consistent with PBCre4 activity, with Foxa1 KO epithelial cells specifically exhibiting altered cell morphology, increased proliferation, and elevated expression of basal cell markers. Castration studies showed that, while PBCre4/Foxa1(loxp/loxp) prostates did not exhibit altered sensitivity in response to hormone ablation compared with control prostates, the number of Foxa1-positive cells in mosaic Foxa1 KO prostates was significantly reduced compared with Foxa1-negative cells following castration. Unexpectedly, gene expression profile analyses revealed that Foxa1 deletion caused abnormal expression of seminal vesicle-associated genes in KO prostates. In summary, these results indicate Foxa1 expression is required for the maintenance of prostatic cellular differentiation.
Department of Pathology, Pennsylvania State University, Hershey, PA, USA.
David J
DJ
DeGraff
Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
Magdalena M
MM
Grabowska
Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
Tom C
TC
Case
Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
Xiuping
X
Yu
Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
Mary K
MK
Herrick
Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
William J
WJ
Hayward
Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
Douglas W
DW
Strand
Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
Justin M
JM
Cates
Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
Simon W
SW
Hayward
Department of Biological Sciences, Rutgers University, Newark, NJ, USA.
Nan
N
Gao
Department Medical Genetics, University of Alberta, Edmonton, AB, USA.
Michael A
MA
Walter
Vancouver Prostate Centre, Vancouver, BC, USA.
Ralph
R
Buttyan
Institute for Integrative Genomics and Department of Medicine, Vanderbilt University, Nashville, TN, USA.
Yajun
Y
Yi
Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
Klaus H
KH
Kaestner
1] Department of Pathology, Pennsylvania State University, Hershey, PA, USA [2] Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA [3] Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Robert J
RJ
Matusik
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D020411:Oligonucleotide Array Sequence Analysis; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012669:Seminal Vesicles / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics
C496500:Foxa1 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; C045073:Cre recombinase; D019426:Integrases