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Cleft palate represents one of the most common congenital birth defects. Transforming growth factor β (TGFβ) signaling plays crucial functions in regulating craniofacial development, and loss of TGFβ receptor type II in cranial neural crest cells leads to craniofacial malformations, including cleft palate in mice (Tgfbr2(fl/fl);Wnt1-Cre mice). Here we have identified candidate target genes of TGFβ signaling during palatal formation. These target genes were selected based on combining results from gene expression profiles of embryonic day 14.5 palates from Tgfbr2(fl/fl);Wnt1-Cre mice and previously identified cleft palate phenotypes in genetically engineered mouse models. We found that fibroblast growth factor 9 (Fgf9) and transcription factor pituitary homeobox 2 (Pitx2) expressions are significantly down-regulated in the palate of Tgfbr2(fl/fl);Wnt1-Cre mice, and Fgf9 and Pitx2 loss of function mutations result in cleft palate in mice. Pitx2 expression is down-regulated by siRNA knockdown of Fgf9, suggesting that Fgf9 is upstream of Pitx2. We detected decreased expression of both cyclins D1 and D3 in the palates of Tgfbr2(fl/fl);Wnt1-Cre mice, consistent with the defect in cell proliferation. Significantly, exogenous FGF9 restores expression of cyclins D1 and D3 in a Pitx2-dependent manner and rescues the cell proliferation defect in the palatal mesenchyme of Tgfbr2(fl/fl);Wnt1-Cre mice. Our study indicates that a TGFβ-FGF9-PITX2 signaling cascade regulates cranial neural crest cell proliferation during palate formation.

Pleuropulmonary Blastoma (PPB) is a pediatric disease that presents with multifocal cystic lung lesions. Familial mutations in DICER1, an essential gene for microRNA synthesis, predisposes to PPB and other related diseases. Loss or mutation of the second copy of DICER1 in developing airway epithelium is thought to initiate cyst formation and increase growth of the underlying mesenchyme. In later stages, additional genetic events in PPB mesenchyme (mutations in the DICER1 RNase IIIb domain or in TP53) can lead to the formation of high-grade sarcomas. We hypothesized that loss of DICER1 function in lung epithelium leads to persistent overgrowth of mesenchyme (and subsequent risk for malignancy), implicating an indirect tumor initiation mechanism. In this study, we show histological and molecular similarity in Type I PPB and mice lacking epithelial Dicer1 or overexpressing epithelial Fibroblast Growth Factor 9 (Fgf9), demonstrate increased FGF9 expression in Type I PPB and in Dicer1-deficient mouse lung epithelium, and show that Fgf9 mediates at least some of the pathology resulting from Dicer1 inactivation in lung epithelium. Finally, we show that specific lung epithelial microRNAs regulate Fgf9. These studies identify FGF9 as a target of DICER1 in lung epithelium that functions as an initiating factor for PPB.

Previous studies on lung development identified a feed forward signaling network that linked FGF9 with mesenchymal FGFR and Wnt/β-Catenin signaling and Fgfr1 and Fgfr2 expression [3, 25]. In this network, FGF9 and mesenchymal FGFR signaling regulated the expression of the canonical Wnt ligand, Wnt2a, and activated mesenchymal Wnt/β-Catenin signaling. Mesenchymal Wnt/β-Catenin signaling, driven by mesenchymal Wnt2a and epithelial Wnt7b, was required for the expression of mesenchymal Fgfr1 and Fgfr2 [3, 21]. To determine if this feed forward loop was activated in lung tissue lacking epithelial Dicer1, we examined expression of Wnt2a and the WNT-responsive transcription factor, Lef1. Compared to control lung (Fig 2A and 2D), ShhCre/+, Dicer1f/f lungs showed increased Wnt2a and Lef1 expression (Fig 2B and 2E). These observations support a model in which upregulation of Fgf9 in ShhCre/+, Dicer1f/f lungs activate mesenchymal FGF-Wnt/β-Catenin signaling.

Embryonic lungs, explanted at E10.5, showed robust mesenchymal growth and epithelial branching over 48 hr in culture. In response to treatment with FGF9, lung explants revealed increased mesenchymal thickness and epithelial airspace dilation [3, 21, 32]. Similar to lung explants treated with FGF9, treatment of E10.5 explants with 100 nM anti-miR-140 or 50 nM of each, anti-miR-140 and anti-miR-328, showed a significant (P

Finally, Fgf9 expression was evaluated in lung explant cultures treated with tiny LNAs. Lungs treated with the LNA-140 (n = 4 of 4) or LNA-140 and LNA-328 (n = 4 of 4) demonstrated increased expression of Fgf9 compared to treatment with control LNA in which only one of seven explants showed Fgf9 expression (Fig 4I and 4J). These data indicated that during ex vivo lung development, miR-140 is sufficient to regulate Fgf9 expression in lung epithelium and regulate mesenchymal growth and epithelial branching.

Progression towards malignancy often involves loss of cellular terminal differentiation. Examination of mesenchymal differentiation into peribronchiolar smooth muscle showed reduced expression of smooth muscle actin (SMA) in peribronchiolar locations in both Type I PPB tissue and mouse lung tissue induced to express FGF9 (Fig 6C and 6I, white arrow). However, vascular SMA expression appeared normal in both mouse and human tissue (Fig 6I, black arrowhead). Markers of proximal-distal epithelial differentiation were similarly altered in both human Type I PPB and FGF9-induced mouse lung. The proximal Club cell secretory protein, CC10, expression was decreased in bronchiolar epithelium (Fig 6D and 6J, white arrow), the distal alveolar Type II cell marker, Sftpc (Fig 6E and 6K, white arrow) and the alveolar Type I cell marker Aquaporin 5 (Aq5) [33] or T1α [34] (Fig 6F and 6L, white arrow) were increased and expanded proximally. Thus, loss of DICER1 in human lung epithelial tissue or overexpression of FGF9 in late stage fetal mouse lung epithelium not only affects mesenchymal growth and differentiation, but also results in distal differentiation of epithelial cell types. The decreased expression of Sftpc in E12.5 lungs that lack Dicer1 (Fig 2G,2H and 2J) likely represents a delay in epithelial differentiation at this stage of development.

Background: The growth of most bony tuberosities, like the deltoid tuberosity (DT), rely on the transmission of muscle forces at the tendon-bone attachment during skeletal growth. Tuberosities distribute muscle forces and provide mechanical leverage at attachment sites for joint stability and mobility. The genetic factors that regulate tuberosity growth remain largely unknown. In mouse embryos with global deletion of fibroblast growth factor 9 (Fgf9), the DT size is notably enlarged. In this study, we explored the tissue-specific regulation of DT size using both global and targeted deletion of Fgf9.

Results: We showed that cell hypertrophy and mineralization dynamics of the DT, as well as transcriptional signatures from skeletal muscle but not bone, were influenced by the global loss of Fgf9. Loss of Fgf9 during embryonic growth led to increased chondrocyte hypertrophy and reduced cell proliferation at the DT attachment site. This endured hypertrophy and limited proliferation may explain the abnormal mineralization patterns and locally dysregulated expression of markers of endochondral development in Fgf9null attachments. We then showed that targeted deletion of Fgf9 in skeletal muscle leads to postnatal enlargement of the DT.

Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9's function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety- and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders.

Fibroblast growth factor 9 (FGF9), originally cloned as glial-activating factor from human glioma cells, is expressed in adult rat brain and kidney. Here we report the chromosomal localization, genomic organization, and embryonic expression pattern of the mouse Fgf9 gene. Fgf9 maps to chromosome 14 near the Ctla6 locus. T