The Drosophila eye has contributed much to our knowledge of cell differentiation. This understanding has primarily come from the study of the R7 photoreceptor; much less is known about the development of the other classes of photoreceptor or the nonneuronal cone or pigment cells. I have used a dominant-negative form of the Drosophila epidermal growth factor receptor (DER) to show that this receptor tyrosine kinase (RTK) is required for the differentiation of all these cell types, and I have also shown that DER is sufficient to trigger their development. DER is even required in R7, where it can replace Sevenless, another RTK. These results broaden our view of eye development to include the whole ommatidium and suggest that reiterative activation of DER is critical for triggering the differentiation of all cell types.

The polytopic membrane protein Rhomboid-1 promotes the cleavage of the membrane-anchored TGFalpha-like growth factor Spitz, allowing it to activate the Drosophila EGF receptor. Until now, the mechanism of this key signaling regulator has been obscure, but our analysis suggests that Rhomboid-1 is a novel intramembrane serine protease that directly cleaves Spitz. In accordance with the putative Rhomboid active site being in the membrane bilayer, Spitz is cleaved within its transmembrane domain, and thus is, to our knowledge, the first example of a growth factor activated by regulated intramembrane proteolysis. Rhomboid-1 is conserved throughout evolution from archaea to humans, and our results show that a human Rhomboid promotes Spitz cleavage by a similar mechanism. This growth factor activation mechanism may therefore be widespread.

The cytokine tumor necrosis factor (TNF) is the primary trigger of inflammation. Like many extracellular signaling proteins, TNF is synthesized as a transmembrane protein; the active signal is its ectodomain, which is shed from cells after cleavage by an ADAM family metalloprotease, TACE/ADAM17. We report that iRhom2/RHBDF2, a proteolytically inactive member of the rhomboid family, is required for TNF release in mice. iRhom2 binds TACE and promotes exit from the endoplasmic reticulum. The failure of TACE ER exit in the absence of iRhom2 prevents furin-mediated maturation and its trafficking to the cell surface, the site of TNF cleavage. Given the role of TNF in autoimmune and inflammatory diseases, iRhom2 may represent an attractive therapeutic target.Proteolytic release of the extracellular domain of transmembrane proteins is an important mechanism for generating signals that regulate major aspects of animal development, physiology, immunity and pathology (1, 2). An important example of regulated ectodomain shedding is the cytokine TNF, the primary trigger of inflammatory responses. TNF is associated with many human diseases including rheumatoid arthritis, Crohn's disease, atherosclerosis, psoriasis, sepsis, diabetes, and obesity. Its blockade is licensed as a therapy for a number of conditions, and is being assessed for others (3). Soluble, active TNF is shed from the plasma membrane by the ADAM family metalloprotease TACE (TNFα converting enzyme; also known as ADAM17) (4). Despite the medical importance of TNF and other transmembrane signaling proteins, the regulation of ectodomain shedding remains poorly understood. Both the transmembrane forms of the signaling proteins themselves, and the shedding proteases, are subject to control by posttranslational modification, interaction with specific partners, and regulated intracellular trafficking and compartmentalization (5-9). The relative physiological importance, however, of these different modes of regulation is unclear.We have investigated the regulation of ectodomain shedding by genetic and cellular approaches, both in Drosophila and mammalian cells. This has led to the recent discovery of a new class of polytopic endoplasmic reticulum (ER) proteins, the iRhoms, which are noncatalytic relatives of rhomboid intramembrane proteases (Fig. 1A) (10). Drosophila iRhom regulates epidermal growth factor (EGF) receptor signaling by interacting with EGF family ligands in the ER, shunting them into the ER-associated degradation (ERAD) pathway (11). iRhoms are conserved in all metazoans, and in cell culture assays their mammalian Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts counterparts, iRhom1 and iRhom2, can also promote ERAD of EGF. In mammals, however, their physiological role is unknown. We therefore generated a null mutation in the gene that encodes iRhom2/RHBDF2 in mice (Fig. S1A). iRhom2 −/− mice appeared normal: they were viable and fertile, with no morphological defects. Unlike iRhom1, which is widely expressed, iRhom2 is...

We present the first measurement of the planet frequency beyond the "snow line," for the planet-to-star mass-ratio interval −4.5 < log q < −2, corresponding to the range of ice giants to gas giants. We find d 2 N pl d log q d log s = (0.36 ± 0.15) dex −2 at the mean mass ratio q = 5 × 10 −4 with no discernible deviation from a flat (Öpik's law) distribution in logprojected separation s. The determination is based on a sample of six planets detected from intensive follow-up observations of high-magnification (A > 200) microlensing events during 2005-2008. The sampled host stars have a typical mass M host ∼ 0.5 M , and detection is sensitive to planets over a range of planet-star-projected separations (s −1 max R E , s max R E), where R E ∼ 3.5 AU (M host /M) 1/2 is the Einstein radius and s max ∼ (q/10 −4.3) 1/3. This corresponds to deprojected separations roughly three times the "snow line." We show that the observations of these events have the properties of a "controlled experiment," which is what permits measurement of absolute planet frequency. High-magnification events are rare, but the survey-plus-follow-up high-magnification channel is very efficient: half of all high-mag events were successfully monitored and half of these yielded planet detections. The extremely high sensitivity of high-mag events leads to a policy of monitoring them as intensively as possible, independent of whether they show evidence of planets. This is what allows us to construct an unbiased sample. The planet frequency derived from microlensing is a factor 8 larger than the one derived from Doppler studies at factor ∼25 smaller star-planet separations (i.e., periods 2-2000 days). However, this difference is basically consistent with the gradient derived from Doppler studies (when extrapolated well beyond the separations from which it is measured). This suggests a universal separation distribution across 2 dex in planet-star separation, 2 dex in mass ratio, and 0.3 dex in host mass. Finally, if all planetary systems were "analogs" of the solar system, our sample would have yielded 18.2 planets (11.4 "Jupiters," 6.4 "Saturns," 0.3 "Uranuses," 0.2 "Neptunes") including 6.1 systems with two or more planet detections. This compares to six planets including one twoplanet system in the actual sample, implying a first estimate of 1/6 for the frequency of solar-like systems.