Fibroblast growth factors (FGFs) are essential molecules for mammalian development. The nine known FGF ligands and the four signaling FGF receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual FGF receptors. To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. We have assayed the mitogenic activity of the nine known FGF ligands on these cell lines. These studies demonstrate that FGF 1 is the only FGF that can activate all FGF receptor splice variants. Using FGF 1 as an internal standard we have determined the relative activity of all the other members of the FGF family. These data should serve as a biochemical foundation for determining developmental, physiological, and pathophysiological processes that involve FGF signaling pathways. Fibroblast growth factor (FGF)1 was identified as an activity that stimulates the proliferation of NIH3T3 cells (1). Currently, FGFs comprise a family of nine structurally related proteins (FGF 1-9). FGFs are expressed in specific spatial and temporal patterns and are involved in developmental processes, angiogenesis, wound healing, and tumorigenesis (2-5).FGFs bind and activate high-affinity receptor tyrosine kinases. The cloning of FGF receptors (FGFRs) has identified four distinct genes (6 -13). These receptors bind members of the FGF family with varying affinity (13-16), and alternative mRNA splicing leads to isoforms of these receptors which have unique ligand binding properties (15,17,18). An additional mechanism regulating FGF activity involves heparin or heparan sulfate proteoglycans, molecules which facilitate ligandreceptor interactions (12,19,20). FGFRs contain an extracellular ligand binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain. The extracellular domain determines ligand binding specificity and mediates ligand-induced receptor dimerization. Dimerization in turn results in one or more trans-phosphorylation events and the subsequent activation of the receptor (21).The extracellular region of the FGFR contains three immunoglobulin-like (Ig-like) domains (6). Alternative mRNA splicing creates several forms of the FGF receptor which differ in their extracellular sequence and have unique ligand binding properties. One splicing event results in the skipping of exons encoding the amino-terminal Ig-like domain (domain I) resulting in a "short" two Ig-like domain form of the receptor (22). The ligand binding properties of the short (two Ig-like domain) and long (three Ig-like domain) FGFRs are similar.2 However, the short form of the receptor may have a higher affinity for some FGFs than the long form (23). Changes in this alternative splicing pattern may correlate with the progression of se...

SUMMARY Cells in intestinal epithelia turn over rapidly due to damage from digestion and toxins produced by the enteric microbiota. Gut homeostasis is maintained by intestinal stem cells (ISCs) that divide to replenish the intestinal epithelium, but little is known about how ISC division and differentiation are coordinated with epithelial cell loss. We show here that when enterocytes (ECs) in the Drosophila midgut are subjected to apoptosis, enteric infection, or JNK-mediated stress signaling, they produce cytokines (Upd, Upd2, Upd3) that activate Jak/Stat signaling in ISCs, promoting their rapid division. Upd/Jak/Stat activity also promotes progenitor cell differentiation, in part by stimulating Delta/Notch signaling, and is required for differentiation in both normal and regenerating midguts. Hence, cytokine-mediated feedback enables stem cells to replace spent progeny as they are lost, thereby establishing gut homeostasis.

Fibroblast growth factor receptor 3 (Fgfr3) is a tyrosine kinase receptor expressed in developing bone, cochlea, brain and spinal cord. Achondroplasia, the most common genetic form of dwarfism, is caused by mutations in FGFR3. Here we show that mice homozygous for a targeted disruption of Fgfr3 exhibit skeletal and inner ear defects. Skeletal defects include kyphosis, scoliosis, crooked tails and curvature and overgrowth of long bones and vertebrae. Contrasts between the skeletal phenotype and achondroplasia suggest that activation of FGFR3 causes achondroplasia. Inner ear defects include failure of pillar cell differentiation and tunnel of Corti formation and result in profound deafness. Our results demonstrate that Fgfr3 is essential for normal endochondral ossification and inner ear development.

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Proper positioning of mitotic spindles ensures equal allocation of chromosomes to daughter cells. This often involves interactions between spindle and astral microtubules and cortical actin. In yeast and Caenorhabditis elegans, some of the protein machinery that connects spindles and cortex has been identified but, in most animal cells, this process remains mysterious. Here, we report that the tumour suppressor homologue APC2 and its binding partner Armadillo both play roles in spindle anchoring during the syncytial mitoses of early Drosophila embryos. Armadillo, alpha-catenin and APC2 all localize to sites of cortical spindle attachment. APC2-Armadillo complexes often localize with interphase microtubules. Zeste-white 3 kinase, which can phosphorylate Armadillo and APC, is also crucial for spindle positioning and regulates the localization of APC2-Armadillo complexes. Together, these data suggest that APC2, Armadillo and alpha-catenin provide an important link between spindles and cortical actin, and that this link is regulated by Zeste-white 3 kinase.