The Eyes Absent phosphatase-transactivator proteins promote proliferation, transformation, migration, and invasion of tumor cells.

The Eyes Absent (EYA) proteins combine transactivation, tyrosine phosphatase, and threonine phosphatase activities in their function as part of a conserved regulatory cascade involved in embryonic organ development. EYA tyrosine phosphatase activity contributes to fly eye development, and vertebrate EYA is involved in promoting DNA damage repair subsequent to genotoxic stress. EYAs are known to be expressed at elevated levels in ovarian and breast cancers. Here, we show that the tyrosine phosphatase activity of the EYAs promotes tumor cell migration, invasion, and transformation. These cellular effects are accompanied by alterations of the actin cytoskeleton and increased levels of active Rac and Cdc42. The invasiveness conferred by EYA is reflected in vivo by inhibition of metastasis seen when EYA3 expression is silenced in the invasive breast cancer cell line MDA-MB-231. Together, our data directly associate the tyrosine phosphatase activity of the EYAs with the oncogenesis-associated cellular properties of motility and invasiveness.

[Tracheal stents for esophagotracheal fistula in laryngectomy patients. Safe fixation to the tracheostoma]. / Trachealstents wegen ösophagotrachealer Fistel beim Laryngektomierten. Sichere Fixierung am Tracheostoma.

BACKGROUND: Postradiotherapy or malignant esophagotracheal fistulas still represent a dilemma. In the absence of surgical options attempts are made to close the fistula endoscopically by means of esophageal and/or tracheal stents. Tracheal stent placement in laryngectomy patients with terminal stomas is particularly problematic due to the risk of stent dislocation during cannula replacement PATIENTS AND METHODS: Six laryngectomy patients with high esophagotracheal fistulas were each fitted with a coated Ultraflex stent (Boston Scientific, Watertown/MA, US). Following skin undermining, the stents were fixed to the tracheostoma with interrupted sutures and the skin flaps attached to the stent with a second row of sutures. RESULTS: Fistulas could be completely closed in all patients and there were no cases of stent dislocation. Cannula replacement was unproblematic. CONCLUSIONS: Suture fixation of tracheal stents is a viable procedure even for patients with esophagotracheal fistulas and terminal tracheostomy following laryngectomy.

[Management of cholecysto- and choledocholithiasis--survey and analysis of 16 615 cholecystectomies and common bile duct explorations in bavaria]. / Aktuelle Therapie der Cholezysto- und Choledocholithiasis - Umfrageergebnisse mit Analyse von 16 615 Eingriffen in Bayern.

BACKGROUND AND METHODS: The aim of this study was the evaluation of the management of cholecysto- and choledocholithiasis and outcome of -laparoscopic as well as open cholecystectomy (CHE) and common bile duct (CBD) exploration in Bavaria, Germany. A written questionnaire -in-cluding 201 structured items was sent to all 180 hospitals and departments performing gen-eral or abdominal surgery in Bavaria. RESULTS: The response rate was 60 %. A total of 16 615 operations for gallstone disease including 16 051 cholecystectomies and 453 CBD explo-ra-tions with or without cholecystectomy were -reported. 88 % of all cholcystectomies started -laparoscopically, the conversion rate was 5.6 %. The Veres needle (69 %), 4 trocar techniques and electrosurgical hook knife were reported as standard procedures. A retrieval bag was used by 53 % of all surgeons. The overall complication rate for cholecystectomy was 5.46 % including 0.15 % -major bile duct injuries. Relaparoscopy was performed in 0.35 %, relaparotomy in 0.44 % and postoperative treatment by ERC in 1.45 %. The overall hospital mortality rate was 0.13 %. When choledocholithiasis was suspected, a two-stage management ("therapeutic splitting") with preoperative ERC was preferred (99 %). The conversion rate of simultaneous laparoscopic CHE+CBD exploration was 43 %. CONCLUSION: These results allow an estimation of the frequency and overall risks in surgical therapy for gallstones. At present, new techniques like combined laparoscopic and endoscopic proce-dures, microinstruments or N.O.T.E.S do not play a significant role in Germany.

[Operative techniques and outcomes in metabolic surgery: sleeve gastrectomy]. / Operative Techniken und deren Outcome in der metabolischen Chirurgie: Sleeve-Gastrektomie.

Laparoscopic sleeve gastrectomy (LSG) was initially introduced for super-obese patients in a two-step concept in order to reduce the perioperative risk. Many years before a very similar technique - the Magenstrasse and Mill (M & M) operation - was developed by Johnston in Leeds / UK as a "more physiological" bariatric procedure with acceptable weight loss, while preserving gastric emptying mechanisms and thus minimising possible side-effects such as vomiting, dumping and diarrhoea, which are common complications of gastric bypass procedures. The following manuscript analyses the current literature and our own preliminary results and parallels publications of the M & M procedure. Until now numerous modifications (e. g., bougie size and residual volume, stapler technique, use of buttress mate-rial) have been reported. However, reported -morbidity and mortality rates were equal to those of gastric banding and gastric bypass (RYGB). In conclusion, laparoscopic sleeve gastrectomy (LSG) has now proven to be as effective as the RYGB for weight loss over a three-year period. Control of hunger and feeling of fullness are -reported to be superior compared to gastric band-ing. Laparoscopic sleeve gastrectomy is no longer an experimental procedure. It should be accepted as one of the effective standard procedures for surgical treatment of morbid obesity.

[Persistent pharyngeocutaneous fistula after transcervical resection of a diverticulum of the hypopharynx]. / Persistierende pharyngokutane Fistel nach Resektion eines Hypopharynxdivertikels.

CASE: A 26-year-old white male patient had undergone resection of a diverticulum of the hypopharynx and myotomy of the cricopharyngeal muscle elsewhere. A transcervical approach had been chosen owing to the presence of an arteria lusoria and the associated risk of vessel injury. The patient had subsequently had recurrent fistulas through the skin incision, which had not resolved despite four further operations. He presented in our department with significant weight loss and persistent retrosternal pain. Esophageal manometry revealed that resting muscle tone in the upper esophageal sphincter was still significantly elevated. Assuming that the earlier myotomy had not been completely successful, we decided to complete this operation as revision surgery. The pharynx was closed with a running suture using the Conley technique. The fistula healed, and there were no further recurrences. CONCLUSION: Complete and careful dissection of all muscle fibers back to the mucosa is essential, as well as complete removal of the diverticulum if this operation is to be successful when performed by the transcutaneous approach. Recurrent diverticula are not the only possible complication; persistent pharyngeocutaneous fistulas can also arise.

[Zenker's diverticulum treated by transoral diverticulostomy: technique and results]. / Die Technik der transoralen Divertikulostomie bei Zenker-Divertikeln - Langzeitresultate und Literaturvergleich.

AIM OF THE STUDY: The surgical technique of transoral diverticulostomy by a modified Endo-GIAtrade mark Stapler (Multifire Endo GIA, Tyco Healthcare) is described. Experiences of this procedure in 31 patients are analysed and compared with different endoscopic and conventional surgical therapies of Zenker's diverticula, which are reported in the literature. METHOD: From January 1996 to December 2005, 31 transoral diverticulostomies were performed. All patients were included porspectively into the study. The median follow-up time after diverticulostomy was 54 months. Manometry, pH-study of the esophagus, endoscopy and swallow radiography were performed before and after surgery. All patients completed the Gastrointestinal quality of live index (GQLI) and the Grosshadern dysphagia score (GHDS). RESULTS: Subjective comfort of the patients as measured by the Smiley Index, the GQLI and the GHDS was increased significantly (p < 0.001) after therapy. Manometry showed that the upper esophageal sphincter functioned normally before and after intervention. A gastrografin swallow excluded leakage at the stapler suture-line in all cases. A conversion to a conventional cricomyotomy with resection of the diverticulum had to be performed once due to a dissection of the esophagus that occurred during insertion of the spreader. In one patient a bleeding out of the suture line was successfully treated with a metal clip. A prothesis broke due to the insertion of the spreader. Two patients developed relapses during the follow-up period of 54 months. CONCLUSION: Compared to standard procedure the endoscopic minimal-invasive therapy proved to be safer. The operation time and the postoperative stay are shorter.

Laparoscopic colonoscopic rendezvous procedures for the treatment of polyps and early stage carcinomas of the colon.

BACKGROUND AND AIMS: Endoscopic treatment of large or colonoscopically inaccessible polyps or early stage tumors in the colon holds the risk of incomplete resection and colonic perforation. The combination of colonoscopy and laparoscopy offers a minimally invasive treatment modality for the complete resection of polyps with low risk. Aim of this study was to assess the feasibility and outcome of patients operated on by laparoendoscopic rendezvous procedures at the colon. MATERIALS AND METHODS: The medical records of 38 patients (21 male, 17 female, median age 66 years [range 39-90]) undergoing rendezvous surgery at the colon were reviewed prospectively. Follow-up data were obtained by clinical examination and personal communication via telephone or questionnaire. The median follow up was 54 months. RESULTS: From January 1998 until April 2007, 38 patients were treated with rendezvous procedures in our hospital. In 30 cases, a colonoscopically assisted laparoscopic procedure was performed and in eight patients a laparoscopically controlled colonoscopic procedure. A benign lesion was confirmed histologically in 31 patients. In five cases, histopathologic diagnosis revealed a malignancy necessitating colonic surgery. A coprolith extraction and a suture of the sigma were performed in one case each. Complications occurred in two patients. One patient developed an anastomosis insufficiency that necessitated a revision. One patient developed pneumonia postoperatively. A conversion to laparotomy had to be performed in two cases. CONCLUSION: Rendezvous procedures offer a safe, minimal-invasive therapeutic approach allowing the resection of benign sessile or colonoscopically inaccessible localized polyps and of early stage colon cancer.

Transoral diverticulostomy with a modified Endo-Gia stapler: results after 4 years of experience.

BACKGROUND: The incidence of Zenker's diverticulum is low (2/100,000). Standard surgical treatment is cricopharyngeal myotomy with diverticulectomy. Various minimally invasive surgical approaches pursued recently have treated Zenker's diverticulum adequately. The functional minimally invasive therapy is performed alternatively using an Endo-Gia stapler inserted transorally to perform an esophageal diverticulostomia, or using thermal coagulation applied by a carbon dioxide (CO2) or argon plasma laser. The key to a successful procedure is adequate exposure of the diverticulum by insertion of a pharynx spreader before the surgery. METHODS: Since 1996, 31 patients who underwent minimally invasive diverticulostomies performed in our clinic have been included prospectively in the current study. All the patients were examined endoscopically before and after surgery. Furthermore, the intraesophageal and intragastric pressure was examined by transesophageal manometry, and the pH in the esophagus and stomach was determined by pH-metry. A barium swallow was performed to exclude leakage at the stapler suture line as proof of sufficient anastomoses. Manometry showed that the upper esophageal sphincter functioned normally before and after surgery. The results were compared with those of patients undergoing conventional procedures. RESULTS: The median follow-up period after resection of the diverticulum was 46 months. Both the Gastrointestinal Quality-of-Life Index (GQLI) (p < 0.001) and the modified dysphagia score (GHDS) increased significantly, indicating that the operations were successful. The minimally invasive procedure is faster than cricopharyngeal myotomy and significantly safer. It is better tolerated by patients, and they are discharged earlier. CONCLUSION: Transoral esophagodiverticulosomy has become the standard procedure for Zenker's diverticulum in the authors' department. The endoscopic minimally invasive approach proved to be safer than standard surgical procedures. It offers a significantly shorter operation time and postoperative hospital stay (p < 0.001).

Laparoscopic partial myectomy: an experimental reflux model.

BACKGROUND: A number of different surgical procedures have been described for the treatment of gastroesophageal reflux disease. Moreover, modifications and completely new techniques are being introduced on a regular basis. Nonetheless, in most cases of novel laparoscopic techniques profound experimental data have not been collected prior to their clinical introduction. Due to the lack of an animal model of inadequate esophageal sphincter function, most experimental studies on antireflux procedures were done on normally functioning esophageal sphincters. METHODS: It is well-known that myotomy alone cannot induce sphincter insufficiency in animal models. In addition, complete myectomy is associated with severe mortality and, therefore, is not useful as an experimental model. This study introduces a new model of laparoscopic partial in vivo myectomy. The procedure described here forms a myectomy of the esophagus using scissors and a sponge on the side of the greater gastric curvature. The size of the myectomy is approximately 6 x 1.5 cm and was successfully performed in a consecutive series of eight experimental animals (male German house pigs). RESULTS: Following an intensive team training on dead animals, the procedure was performed with success via the laparoscope in all study animals (n = 8). The sphincter pressure as determined by manometry was significantly reduced from 7.7 mmHg (range, 4.5-9.1; preoperative values) to 2.2 mmHg (range, 0-6.8; early postoperative values) and 2.3 mmHg (range, 0-3.7) at 8 weeks after surgery (p < 0.001). In addition, the length of the lower esophageal sphincter as well as the sphincter pressure vector volume were significantly reduced early as well as at 8 weeks after laparoscopic myectomy. Furthermore, endoscopy and reflux testing were pathologic compared with control animals. CONCLUSIONS: Laparoscopic partial myectomy results in complete sphincter insufficiency with only little procedure-related morbidity. This procedure allows for the experimental evaluation of surgical procedures on the gastroesophageal junction. Future modifications of surgical antireflux procedures can therefore be evaluated in an experimental setting prior to their clinical introduction.

How safe are laparoscopic intracorporeal anastomoses?

BACKGROUND: A recent German Multicenter Study comprising 3 070 laparoscopic colorectal resections indicates that complete intracorporeal anastomoses are performed in only 1.8 % cases. The aim of our study was to review and analyse the safety of complete intracorpeal anastomosis. METHODS: In a literature survey we searched for complete intracorporeal anastomosis with different key words. RESULTS: In agreement with the literature, technically demanding hand-sutured anastomoses are no common practice. Intracorporeal anastomosis is usually done using endoscopic linear stapling devices or a conventional circular stapler by performing end-to-end, end-to-side, and side-to-side anastomoses. These techniques are more frequently used in the upper than in the lower gastrointestinal tract. CONCLUSIONS: The data published so far, however, indicates that completely intracorporeal performed anastomoses are safe in the hands of laparoscopically experienced surgeons. This technique implies very low percentages of postoperative stenoses (0-10 %) and, furthermore, very low percentages of postoperative anastomotic leakages (0-8 %).

Tyrosine phosphorylation sites on FRS2alpha responsible for Shp2 recruitment are critical for induction of lens and retina.

Early development of the lens and retina depends upon reciprocal inductive interactions between the embryonic surface ectoderm and the underlying neuroepithelium of the optic vesicle. FGF signaling has been implicated in this signal exchange. The docking protein FRS2alpha is a major mediator of FGF signaling by providing a link between FGF receptors (FGFRs) and a variety of intracellular signaling pathways. After FGF stimulation, tyrosine-phosphorylated FRS2alpha recruits four molecules of the adaptor protein Grb2 and two molecules of the protein tyrosine phosphatase Shp2, resulting in activation of the Ras/extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3 kinase/Akt signaling pathways. In this report, we explore the role of signaling pathways downstream of FRS2alpha in eye development by analyzing the phenotypes of mice that carry point mutations in either the Grb2-(Frs2alpha(4F)) or the Shp2-binding sites (Frs2alpha(2F)) of FRS2alpha. Although Frs2alpha(4F/4F) mice exhibited normal early eye development, all Frs2alpha(2F/2F) embryos were defective in eye development and showed anophthalmia or microphthalmia. Consistent with the critical role of FRS2alpha in FGF signaling, the level of activated extracellular signal-regulated kinase in Frs2alpha(2F/2F) embryos was significantly lower than that observed in wild-type embryos. Furthermore, expression of Pax6 and Six3, molecular markers for lens induction, were decreased in the Frs2alpha(2F/2F) presumptive lens ectoderm. Similarly, the expression of Chx10 and Bmp4, genes required for retinal precursor proliferation and for lens development, respectively, was also decreased in the optic vesicles of Frs2alpha(2F/2F) mice. These experiments demonstrate that intracellular signals that depend on specific tyrosine residues in FRS2alpha lie upstream of gene products critical for induction of lens and retina.

Early eye development in vertebrates.

This review provides a synthesis that combines data from classical experimentation and recent advances in our understanding of early eye development. Emphasis is placed on the events that underlie and direct neural retina formation and lens induction. Understanding these events represents a longstanding problem in developmental biology. Early interest can be attributed to the curiosity generated by the relatively frequent occurrence of disorders such as cyclopia and anophthalmia, in which dramatic changes in eye development are readily observed. However, it was the advent of experimental embryology at the turn of the century that transformed curiosity into active investigation. Pioneered by investigators such as Spemann and Adelmann, these embryological manipulations have left a profound legacy. Questions about early eye development first addressed using tissue manipulations remain topical as we try to understand the molecular basis of this process.

The upstream ectoderm enhancer in Pax6 has an important role in lens induction.

The Pax6 gene has a central role in development of the eye. We show, through targeted deletion in the mouse, that an ectoderm enhancer in the Pax6 gene is required for normal lens formation. Ectoderm enhancer-deficient embryos exhibit distinctive defects at every stage of lens development. These include a thinner lens placode, reduced placodal cell proliferation, and a small lens pit and lens vesicle. In addition, the lens vesicle fails to separate from the surface ectoderm and the maturing lens is smaller and shows a delay in fiber cell differentiation. Interestingly, deletion of the ectoderm enhancer does not eliminate Pax6 production in the lens placode but results in a diminished level that, in central sections, is apparent primarily on the nasal side. This argues that Pax6 expression in the lens placode is controlled by the ectoderm enhancer and at least one other transcriptional control element. It also suggests that Pax6 enhancers active in the lens placode drive expression in distinct subdomains, an assertion that is supported by the expression pattern of a lacZ reporter transgene driven by the ectoderm enhancer. Interestingly, deletion of the ectoderm enhancer causes loss of expression of Foxe3, a transcription factor gene mutated in the dysgenetic lens mouse. When combined, these data and previously published work allow us to assemble a more complete genetic pathway describing lens induction. This pathway features (1) a pre-placodal phase of Pax6 expression that is required for the activity of multiple, downstream Pax6 enhancers; (2) a later, placodal phase of Pax6 expression regulated by multiple enhancers; and (3) the Foxe3 gene in a downstream position. This pathway forms a basis for future analysis of lens induction mechanism.

Fgf receptor signaling plays a role in lens induction.

We describe experiments showing that fibroblast growth factor receptor (Fgfr) signaling plays a role in lens induction. Three distinct experimental strategies were used: (1) using small-molecule inhibitors of Fgfr kinase activity, we showed that both the transcription level and protein expression of Pax6, a transcription factor critical for lens development, was diminished in the presumptive lens ectoderm; (2) transgenic mice (designated Tfr7) that expressed a dominant-negative Fgf receptor exclusively in the presumptive lens ectoderm showed defects in formation of the lens placode at E9.5 but in addition, showed reduced levels of expression for Pax6, Sox2 and Foxe3, all markers of lens induction; (3) by performing crosses between Tfr7 transgenic and Bmp7-null mice, we showed that there is a genetic interaction between Fgfr and Bmp7 signaling at the induction phases of lens development. This manifested as exacerbated lens development defects and lower levels of Pax6 and Foxe3 expression in Tfr7/Tfr7, Bmp7(+/-) mice when compared with Tfr7/Tfr7 mice alone. As Bmp7 is an established lens induction signal, this provides further evidence that Fgfr activity is important for lens induction. This analysis establishes a role for Fgfr signaling in lens induction and defines a genetic pathway in which Fgfr and Bmp7 signaling converge on Pax6 expression in the lens placode with the Foxe3 and Sox2 genes lying downstream.

Misexpression of IGF-I in the mouse lens expands the transitional zone and perturbs lens polarization.

Insulin-like growth factor-I (IGF-I) has been implicated as a regulator of lens development. Experiments performed in the chick have indicated that IGF-I can stimulate lens fiber cell differentiation and may be involved in controlling lens polarization. To assess IGF-I activity on mammalian lens cells in vivo, we generated transgenic mice in which this factor was overexpressed from the alphaA-crystallin promoter. Interestingly, we observed no premature differentiation of lens epithelial cells. The pattern of lens polarization was perturbed, with an apparent expansion of the epithelial compartment towards the posterior lens pole. The distribution of immunoreactivity for MIP26 and p57(KIP2) and a modified pattern of proliferation suggested that this morphological change was best described as an expansion of the germinative and transitional zones. The expression of IGF-I signaling components in the normal transitional zone and expansion of the transitional zone in the transgenic lens both suggest that endogenous IGF-I may provide a spatial cue that helps to control the normal location of this domain.

[How safe is intracorporeal anastomosis?]. / Wie sicher ist die intrakorporale Anastomosierung?

A recent German multi-centre study comprising 3070 laparoscopic colorectal resections indicates that complete intracorporeal anastomoses are done in only 1.8%. In agreement with the literature, technically demanding hand-sutured anastomoses are no common practice either. Intracorporeal anastomosis is usually done using endoscopic linear stapling devices or the conventional circular stapler by performing end-to-end, end-to-side, and side-to-side anastomoses. These techniques are more frequently used in the upper than in the lower gastrointestinal tract. The date published so far, however, indicate that the complete intracorporeal anastomosis is a save technique in the hands of laparoscopically experienced surgical teams. This technique has very low rates of postoperative stenoses (0-10%) and, furthermore, very low rates of postoperative anastomotic leakages (0-8%).

The role of carcinoembryonic antigen for the detection of recurrent disease following curative resection of large-bowel cancer.

BACKGROUND AND AIMS: During recent years, a discussion about cost-effectiveness and importance of follow-up evaluation after curative resection of large-bowel cancer has developed. It is not known whether the determination of carcino-embryonic antigen (CEA) plays a crucial role in the early detection of recurrent disease. PATIENTS/METHODS: We conducted an analysis of the prospective follow-up database of 1321 patients after curative resection of colorectal cancer in our institution between 1990 and 1998 to evaluate the role of CEA in the early detection of recurrent disease. RESULTS: Of the 1321 patients included in our study, 306 developed recurrent disease following curative resection (23.2%). These patients with recurrent disease were divided into: Group I. No pre-operative CEA determination/insufficient follow-up (n=47; 15.4%). Group II. No elevation of CEA with primary cancer (n=156; 51.0%): (IIa) elevation with recurrent disease (n=62); (IIb) no elevation at any time point (n=53); and (IIc) role of CEA not completely elucidated (n=41). Thirteen patients of group II underwent curative relapse surgery (8.3%). Group III. Elevated CEA with primary cancer (n=103; 33.7%): (IlIa) no increase with recurrent disease (n=21); (IIIb) increase with other symptoms of recurrent disease (n=45); and (IIIc) increased values as an early symptom of recurrent disease (n=37). Sixteen patients of group III underwent curative relapse surgery (15.5%). In patients after relapse surgery, recurrent disease developed again after a median time of 12 months (mean 17.9+/-3.8 months). CONCLUSIONS: Our findings indicate that 2.8% of all patients (12.1% of patients with recurrent disease) who underwent curative resection of colorectal cancer profit from follow-up CEA determinations. With careful observation of CEA kinetics, 6.2% (n=82) of all patients or 26.8% of patients with recurrent disease could profit from routine follow-up CEA determinations. In 9.5% of patients with recurrent disease, curative resection of relapse was achieved and these patients remained disease free for a median time of 12 months. Regular CEA measurements remain an important part of routine patient care after curative resection of colorectal cancer.

Endogenous and ectopic gland induction by FGF-10.

FGF-10, a member of the fibroblast growth factor family, is expressed in mesodermally derived cell populations during embryogenesis. During normal ocular development, FGF-10 is expressed in the perioptic mesenchyme adjacent to the Harderian and lacrimal gland primordia. In this report, we provide evidence that FGF-10 is both necessary and sufficient to initiate glandular morphogenesis. Lens-specific expression of FGF-10 was sufficient to induce ectopic ocular glands within the cornea. In addition, lacrimal and Harderian glands were not seen in FGF-10 null fetuses. Based on these results we propose that FGF-10 is an inductive signal that initiates ocular gland morphogenesis.

FGF10 is an inducer and Pax6 a competence factor for lacrimal gland development.

We investigated the mechanism of tissue induction and specification using the lacrimal gland as a model system. This structure begins its morphogenesis as a bud-like outgrowth of the conjunctival epithelium and ultimately forms a branched structure with secretory function. Using a reporter transgene as a specific marker for gland epithelium, we show that the transcription factor Pax6 is required for normal development of the gland and is probably an important competence factor. In investigating the cell-cell signaling required, we show that fibroblast growth factor (FGF) 10 is sufficient to stimulate ectopic lacrimal bud formation in ocular explants. Expression of FGF10 in the mesenchyme adjacent to the presumptive lacrimal bud and absence of lacrimal gland development in FGF10-null mice strongly suggest that it is an endogenous inducer. This was supported by the observation that inhibition of signaling by a receptor for FGF10 (receptor 2 IIIb) suppressed development of the endogenous lacrimal bud. In explants of mesenchyme-free gland epithelium, FGF10 stimulated growth but not branching morphogenesis. This suggested that its role in induction is to stimulate proliferation and, in turn, that FGF10 combines with other factors to provide the instructive signals required for lacrimal gland development.