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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2008.04.009 Byline: Yongjun Yin (a), Andrew C. White (a), Sung-Ho Huh (a), Matthew J. Hilton (b), Hidemi Kanazawa (a), Fanxin Long (a)(b), David M. Ornitz (a) Keywords: Fibroblast growth factor 9 (FGF9); Fibroblast growth factor receptor (FGFR); Wnt2a; Wnt7b; [beta]-Catenin; Lung development; Mesenchyme Abstract: Lung mesenchyme is a critical determinant of the shape and size of the lung, the extent and patterning of epithelial branching, and the formation of the pulmonary vasculature and interstitial mesenchymal components of the adult lung. Fibroblast growth factor 9 (FGF9) is a critical regulator of lung mesenchymal growth; however, upstream mechanisms that modulate the FGF mesenchymal signal and the downstream targets of mesenchymal FGF signaling are poorly understood. Here we have identified a robust regulatory network in which mesenchymal FGF signaling regulates [beta]-Catenin mediated WNT signaling in lung mesenchyme. By conditionally inactivating [beta]-Catenin in lung mesenchyme, we show that mesenchymal WNT-[beta]-Catenin signaling is essential for lung development and acts to regulate the cell cycle G1 to S transition and the FGF responsiveness of mesenchyme. Together, both FGF and WNT signaling pathways function to sustain mesenchymal growth and coordinate epithelial morphogenesis during the pseudoglandular stage of lung development. Author Affiliation: (a) Department of Developmental Biology, Washington University School of Medicine, Campus Box 8103, 660 S. Euclid Avenue, St. Louis, MO 63110, USA (b) Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA Article History: Received 10 March 2008; Revised 3 April 2008; Accepted 7 April 2008

Summary: The identity of niche signals necessary to maintain embryonic nephron progenitors is unclear. Here we provide evidence that Fgf20 and Fgf9, expressed in the niche, and Fgf9, secreted from the adjacent ureteric bud, are necessary and sufficient to maintain progenitor stemness. Reduction in the level of these redundant ligands in the mouse led to premature progenitor differentiation within the niche. Loss of FGF20 in humans, or of both ligands in mice, resulted in kidney agenesis. Sufficiency was shown in vitro where Fgf20 or Fgf9 (alone or together with Bmp7) maintained isolated metanephric mesenchyme or sorted nephron progenitors that remained competent to differentiate in response to Wnt signals after 5 or 2 days in culture, respectively. These findings identify a long-sought-after critical component of the nephron stem cell niche and hold promise for long-term culture and utilization of these progenitors in vitro. [Copyright &y& Elsevier]

Mammalian cochlear development encompasses a series of morphological and molecular events that results in the formation of a highly intricate structure responsible for hearing. One remarkable event occurs during development is the cochlear lengthening that starts with cochlear outgrowth around E11 and continues throughout development. Different mechanisms contribute to this process including cochlear progenitor proliferation and convergent extension. We previously identified that FGF9 and FGF20 promote cochlear lengthening by regulating auditory sensory epithelial proliferation through FGFR1 and FGFR2 in the periotic mesenchyme. Here, we provide evidence that ETS-domain transcription factors ETV4 and ETV5 are downstream of mesenchymal FGF signaling to control cochlear lengthening. Next generation RNA sequencing identified that Etv1 , Etv4 and Etv5 mRNAs are decreased in the Fgf9 and Fgf20 double mutant periotic mesenchyme. Deleting both Etv4 and Etv5 in periotic mesenchyme resulted in shortening of cochlear length but maintaining normal patterning of organ of Corti and density of hair cells and supporting cells. This recapitulates phenotype of mesenchymal-specific Fgfr1 and Fgfr2 deleted inner ear. Furthermore, analysis of Etv1/4/5 triple conditional mutants revealed that ETV1 does not contribute in this process. Our study reveals that ETV4 and ETV5 function downstream of mesenchymal FGF signaling to promote cochlear lengthening. • RNA sequencing reveals genes differentially expressed in Fgf9/20 mutant inner ears. • FGF9/20 regulates expression ETV1/4/5. • Loss of Etv4/5 in peri-otic mesenchyme shortens cochlear length. • Etv1 does not contribute cochlear length maintenance. [ABSTRACT FROM AUTHOR]

Summary The olfactory epithelium (OE) is a neurosensory organ required for the sense of smell. Turbinates, bony projections from the nasal cavity wall, increase the surface area within the nasal cavity lined by the OE. Here, we use engineered fibroblast growth factor 20 (Fgf20) knockin alleles to identify a population of OE progenitor cells that expand horizontally during development to populate all lineages of the mature OE. We show that these Fgf20 -positive epithelium-spanning progenitor (FEP) cells are responsive to Wnt/β-Catenin signaling. Wnt signaling suppresses FEP cell differentiation into OE basal progenitors and their progeny and positively regulates Fgf20 expression. We further show that FGF20 signals to the underlying mesenchyme to regulate the growth of turbinates. These studies thus identify a population of OE progenitor cells that function to scale OE surface area with the underlying turbinates. Graphical Abstract Highlights • Fgf20 -positive epithelial-spanning progenitor (FEP) cells form olfactory epithelium • FEP cells regulate turbinate growth via FGF20 • Wnt/βCat signaling maintains FEP cells in an undifferentiated state • Wnt/βCat signaling regulates the expression of FGF20 Mechanisms regulating olfactory epithelium expansion and turbinate growth are poorly understood. In this issue of Developmental Cell , Yang et al. show that an Fgf20 -expressing progenitor (FEP) expands the olfactory epithelium and regulates turbinate growth via FGF20. Furthermore, Wnt/β-Catenin signaling acts as a master regulator of these two processes. [ABSTRACT FROM AUTHOR]

TIP30 (30 kDa HIV-1 TAT-interacting protein), also called HTATIP2 or CC3, is a tumor suppressor protein that acts as an angiogenesis inhibitor. TIP30 blocks nuclear import of the mRNA-binding protein HuR, and thereby promotes the cytoplasmic accumulation of HuR by binding to importin-β, which is known to facilitate the cytoplasm-tonuclear transport of HuR. Accumulation of HuR in the cytoplasm, in turn, enhances the expression of the transcription factor p53, a tumor suppressor that plays an essential role in preserving genome stability and inhibiting cancer growth. In addition to such a post-transcriptional mechanism via which TIP30 increases the p53 level, it has been proposed that TIP30 may regulate p53 protein at the protein level by directly binding to it. In order to investigate the possibility of direct interaction between p53 and TIP30, we have used on three functional regions in p53 and examined their interactions with TIP30 using GST pull-down assay and surface plasmon resonance technique. The results show that that TIP30 binds to the DNA-binding domain and the C-terminal domain of p53. [ABSTRACT FROM AUTHOR]