FGF8 is essential for formation of the ductal system in the male reproductive tract

Kitagaki, Jirouta; Ueda, Yutaka; Chi, Xuan; Sharma, Nirmala; Elder, C. M.; Truffer, Erika; Costantini, Frank; Lewandoski, Mark; Perantoni, Alan O.

doi:10.1242/dev.051888

Cited by 24 publications

(22 citation statements)

References 55 publications

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“…5E–H). Fgf8 is expressed in and essential for the formation of cranial MTs (Kitagaki et al, 2011; Perantoni et al, 2005). Fgf8 was ectopically expressed throughout the IM in Shh KO embryos (Fig.…”

Section: Resultsmentioning

confidence: 99%

Midline-derived Shh regulates mesonephric tubule formation through the paraxial mesoderm

Murashima

Akita

Okazawa

et al. 2014

Developmental Biology

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During organogenesis, Sonic hedgehog (Shh) possesses dual functions: Shh emanating from midline structures regulates the positioning of bilateral structures at early stages, whereas organ-specific Shh locally regulates organ morphogenesis at later stages. The mesonephros is a transient embryonic kidney in amniote, whereas it becomes definitive adult kidney in some anamniotes. Thus, elucidating the regulation of mesonephros formation has important implications for our understanding of kidney development and evolution. In Shh knockout (KO) mutant mice, the mesonephros was displaced towards the midline and ectopic mesonephric tubules (MTs) were present in the caudal mesonephros. Mesonephros-specific ablation of Shh in Hoxb7-Cre;Shhflox/− and Sall1CreERT2/+;Shhflox/− mice embryos indicated that Shh expressed in the mesonephros was not required for either the development of the mesonephros or the differentiation of the male reproductive tract. Moreover, stage-specific ablation of Shh in ShhCreERT2/flox mice showed that notochord- and/or floor plate-derived Shh were essential for the regulation of the number and position of MTs. Lineage analysis of hedgehog (Hh)-responsive cells, and analysis of gene expression in Shh KO embryos suggested that Shh regulated nephrogenic gene expression indirectly, possibly through effects on the paraxial mesoderm. These data demonstrate the essential role of midline-derived Shh in local tissue morphogenesis and differentiation.

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Section: Resultsmentioning

confidence: 99%

Midline-derived Shh regulates mesonephric tubule formation through the paraxial mesoderm

Murashima

Akita

Okazawa

et al. 2014

Developmental Biology

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“…Coiling and spatial arrangement of epididymal duct are governed by a complex signaling network involving testosterone signaling and a number of developmental signaling pathways (Cornwall, 2009; Di Giovanni et al, 2011; Hsia and Cornwall, 2004; Joseph et al, 2009; Kitagaki et al, 2011; Tomaszewski et al, 2007; Xu et al, 2010). Here we showed that Pkd1 is also an essential player in this regulatory network.…”

Section: Discussionmentioning

confidence: 99%

Pkd1 is required for male reproductive tract development

Nie

Arend

2013

Mechanisms of Development

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Reproductive tract abnormalities and male infertility have higher incidence in autosomal dominant polycystic kidney disease (ADPKD) patients than in general population. In this work, we revealed that Pkd1, whose mutations account for 85% of ADPKD cases, is essential for male reproductive tract development. Disruption of Pkd1 caused a spectrum of defects in the murine male reproductive tract. The earliest visible defect in Pkd1-/- reproductive tract was cystic dilation of the efferent ducts, which are derivatives of the mesonephric tubules. Epididymis development was delayed or arrested in the Pkd1-/- mice. No sign of epididymal coiling was seen in the Pkd1 null mice. Disruption of Pkd1 in epithelia alone using the Pax2-cre mice was sufficient to cause efferent duct dilation and coiling defect in the epididymis, suggesting that Pkd1 is critical for epithelial development and maintenance in male reproductive tract. In-depth analysis showed that Pkd1 is required to maintain tubulin cytoskeleton and important for Tgf-β/Bmp signal transduction in the epithelia of male reproductive tract. Altogether, our results provide the first direct evidence for developmental roles of Pkd1 in male reproductive tract and provide new insights in reproductive tract abnormalities and infertility in ADPKD patients.

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“…Previous studies have surveyed the expression of growth factors in the epididymis and indicated the regional specific expression patterns for several growth factors [18,19]. A recent knockout study demonstrated that FGF8, which is expressed in the male reproductive tract, was essential for the formation of the ductal system in the epididymis, vas deferens, and efferent ducts [20]. Overexpression of FGF8b caused progressive stromal and epithelial changes in the epididymis in transgenic mice [21].…”

Section: Regulation Of the Basal Activity Level Of The Components Of mentioning

confidence: 99%

The Role of Fibroblast Growth Factor Receptor Substrate 2 (FRS2) in the Regulation of Two Activity Levels of the Components of the Extracellular Signal-Regulated Kinase (ERK) Pathway in the Mouse Epididymis1

Yang

Hinton

2013

Biology of Reproduction

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The components of the extracellular signal-regulated kinase (ERK) pathway are involved in the regulation of epididymal cellular processes. Interestingly, our previous studies showed that there are two different activity levels of the ERK pathway components in the epididymal epithelium: a basal level in most regions and a higher level in the differentiated initial segment (IS). In this study we analyzed the role of fibroblast growth factor receptor substrate 2 (FRS2) in the regulation of these two levels. Two mouse models were generated. In the first model, Frs2 was deleted from epithelial cells of most epididymal regions except for the IS from the embryonic period onward. Loss of Frs2 dampened the basal activity level of the ERK pathway components, which resulted in an increase in apoptosis along the epididymal duct. This was observed during the period when FRS2 expression level was highest in wild-type epididymides. In the second model, Frs2 was deleted from the proximal epididymal epithelium from Postnatal Day 17 onward. Most of the epididymides in this model exhibited normal morphology. Loss of Frs2 in these epididymides did not affect the high activity level of the ERK pathway components in the IS. However, a subgroup of epididymides in the second model showed increased apoptosis which resulted in an abnormally shaped proximal region or development of granulomas. Therefore, data from these two models showed that FRS2 played different roles in the regulation of two activity levels of the ERK pathway components in the epididymis.

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FGF8 is essential for formation of the ductal system in the male reproductive tract

Cited by 24 publications

References 55 publications

Midline-derived Shh regulates mesonephric tubule formation through the paraxial mesoderm

Midline-derived Shh regulates mesonephric tubule formation through the paraxial mesoderm

Pkd1 is required for male reproductive tract development

The Role of Fibroblast Growth Factor Receptor Substrate 2 (FRS2) in the Regulation of Two Activity Levels of the Components of the Extracellular Signal-Regulated Kinase (ERK) Pathway in the Mouse Epididymis1

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