Epithelial Bmp (Bone morphogenetic protein) signaling for bulbourethral gland development: A mouse model for congenital cystic dilation

Omori, Akiko; Harada, Mikio; Ohta, Sho; Villacorte, Mylah; Sugimura, Yoshiki; Shiraishi, Takeshi; Suzuki, Kentaro; Nakagata, Naomi; Ito, Takaaki; Yamada, Gen

doi:10.1111/j.1741-4520.2011.00318.x

Cited by 6 publications

(9 citation statements)

References 40 publications

(105 reference statements)

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“…To introduce the mutation for Bmpr1a specifically in prostatic epithelial cells, Bmpr1a -floxed mice were intercrossed with ShhCreERT2 driver mice, and tamoxifen was administrated at E9.5. The Cre driver mice strain introduces the recombination in the endodermal urogenital sinus epithelium (19), which is the origin of prostatic epithelial (both basal and luminal) cells (1) but not in the stromal cells. The recombination was confirmed using R26RYFP indicator allele and monitoring the expression of yellow fluorescent protein in the AP at P14 (Figure 2, A and B).…”

Section: Resultsmentioning

confidence: 99%

“…Tamoxifen (Sigma) was dissolved in sesame oil (Kanto Chemical) to a final concentration of 20 mg/mL. Four milligrams of tamoxifen per 40 g body weight was administrated (ip) to the pregnant mice at E9.5 (19). Tamoxifen-treated dams often experience dystocia and their pups died (data not shown) (42).…”

Section: Methodsmentioning

confidence: 99%

“…Tissues were harvested as described previously and fixed in 4% paraformaldehyde at 4°C (19). The tissue specimens were then dehydrated, embedded in paraffin, and sectioned with thickness of 6 μm.…”

Section: Methodsmentioning

confidence: 99%

“…Both mouse models exhibit increased prostatic branching. Bmpr1a mediates various functions during development of urogenital organs derived from urogenital sinus (19, 20). However, no mutant mouse models of the Bmp receptors have been investigated for prostatic development.…”

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Essential Roles of Epithelial Bone Morphogenetic Protein Signaling During Prostatic Development

et al. 2014

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Prostate is a male sex-accessory organ. The prostatic epithelia consist primarily of basal and luminal cells that differentiate from embryonic urogenital sinus epithelia. Prostate tumors are believed to originate in the basal and luminal cells. However, factors that promote normal epithelial differentiation have not been well elucidated, particularly for bone morphogenetic protein (Bmp) signaling. This study shows that Bmp signaling prominently increases during prostatic differentiation in the luminal epithelia, which is monitored by the expression of phosphorylated Smad1/5/8. To elucidate the mechanism of epithelial differentiation and the function of Bmp signaling during prostatic development, conditional male mutant mouse analysis for the epithelial-specific Bmp receptor 1a (Bmpr1a) was performed. We demonstrate that Bmp signaling is indispensable for luminal cell maturation, which regulates basal cell proliferation. Expression of the prostatic epithelial regulatory gene Nkx3.1 was significantly reduced in the Bmpr1a mutants. These results indicate that Bmp signaling is a key factor for prostatic epithelial differentiation, possibly by controlling the prostatic regulatory gene Nkx3.1.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Essential Roles of Epithelial Bone Morphogenetic Protein Signaling During Prostatic Development

et al. 2014

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“…Such organs are essential for the transfer of urine from the renal pelvis toward the bladder. Previous studies have suggested that growth factors, such as Sonic hedgehog (Shh) and Bone morphogenetic proteins (Bmps) are essential for the formation of the urinary tract [1]–[9]. The loss of such signaling in genetically-engineered mice phenocopied human urinary diseases, such as congenital anomalies of the kidney and urinary tract (CAKUT) or the VACTERL syndrome [1], [10]–[14].…”

Section: Introductionmentioning

confidence: 99%

The Hedgehog Signal Induced Modulation of Bone Morphogenetic Protein Signaling: An Essential Signaling Relay for Urinary Tract Morphogenesis

et al. 2012

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BackgroundCongenital diseases of the urinary tract are frequently observed in infants. Such diseases present a number of developmental anomalies such as hydroureter and hydronephrosis. Although some genetically-modified mouse models of growth factor signaling genes reproduce urinary phenotypes, the pathogenic mechanisms remain obscure. Previous studies suggest that a portion of the cells in the external genitalia and bladder are derived from peri-cloacal mesenchymal cells that receive Hedgehog (Hh) signaling in the early developmental stages. We hypothesized that defects in such progenitor cells, which give rise to urinary tract tissues, may be a cause of such diseases.Methodology/Principal FindingsTo elucidate the pathogenic mechanisms of upper urinary tract malformations, we analyzed a series of Sonic hedgehog (Shh) deficient mice. Shh−/− displayed hydroureter and hydronephrosis phenotypes and reduced expression of several developmental markers. In addition, we suggested that Shh modulation at an early embryonic stage is responsible for such phenotypes by analyzing the Shh conditional mutants. Tissue contribution assays of Hh-responsive cells revealed that peri-cloacal mesenchymal cells, which received Hh signal secreted from cloacal epithelium, could contribute to the ureteral mesenchyme. Gain- and loss-of-functional mutants for Hh signaling revealed a correlation between Hh signaling and Bone morphogenetic protein (Bmp) signaling. Finally, a conditional ablation of Bmp receptor type IA (BmprIA) gene was examined in Hh-responsive cell lineages. This system thus made it possible to analyze the primary functions of the growth factor signaling relay. The defective Hh-to-Bmp signaling relay resulted in severe urinary tract phenotypes with a decrease in the number of Hh-responsive cells.Conclusions/SignificanceThis study identified the essential embryonic stages for the pathogenesis of urinary tract phenotypes. These results suggested that Hh-responsive mesenchymal Bmp signaling maintains the population of peri-cloacal mesenchyme cells, which is essential for the development of the ureter and the upper urinary tract.

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Expression of transforming growth factor β and fibroblast growth factor 2 in the lens epithelium of Morioka cataract mice

Kondo

Ishiga-Hashimoto

Nagai

et al. 2014

Congenital Anomalies

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In the Morioka cataract (MCT) mice, lensopacity appears at 6 to 8 weeks of age, and swollen lens fiber is electron-microscopically observed at 3 weeks after birth. The present study was designed to characterize the expression of transforming growth factor β (TGFβ) and fibroblast growth factor 2 (FGF2) in the lens epithelium of the MCT mice. Immunohistochemical analysis showed that the expression of TGFβ in the lens epithelium of the MCT mice was stronger than that of the wild-type ddY mice at 2 and 4 weeks after birth. The expression of TGFβ receptors (TGFβRI and TGFβRII) and FGF2 in the lens epithelium of the MCT mice was stronger than that of the wild-type ddY mice at 4 weeks and weaker than that of the wild-type ddY mice at 15 weeks after birth. Using real time polymerase chain reaction (PCR), quantitative RT-PCR analysis showed that expression of TGFβ1 and TGFβ2 mRNA in the lens of 2-week-old MCT mice was significantly higher compared to age-matched wildtype ddY mice. These findings indicate that the lens epithelium of MCT mice has increased expression of TGFβ before cataract affection and that changes in the expression of FGF2 as well as TGFβ may contribute to the progression of the cataract in the mice.

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Epithelial Bmp (Bone morphogenetic protein) signaling for bulbourethral gland development: A mouse model for congenital cystic dilation

Cited by 6 publications

References 40 publications

Essential Roles of Epithelial Bone Morphogenetic Protein Signaling During Prostatic Development

Essential Roles of Epithelial Bone Morphogenetic Protein Signaling During Prostatic Development

The Hedgehog Signal Induced Modulation of Bone Morphogenetic Protein Signaling: An Essential Signaling Relay for Urinary Tract Morphogenesis

Expression of transforming growth factor β and fibroblast growth factor 2 in the lens epithelium of Morioka cataract mice

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