INTRODUCTIONEpithelia are one of the universal architectural units used in thedevelopment and maintenance of animal form. Epithelial cellsare arranged in sheets that have distinct apical-basal polarity.The different shapes of organs develop from the regulatedmolding of epithelial structure via tissue-specific morpho-genetic programs. These programs govern the complex inte-gration of epithelial cell behaviors, including division,rearrangement, shape, shape changes and the recruitment orloss of cells from the epithelium.As a model to understand epithelial morphogenesis, we areanalyzing the simple monolayer follicular epithelium thatdevelops in concert with the differentiating germline duringDrosophila oogenesis. The follicular epithelium has develop-mental, morphological, and molecular properties of vertebrateepithelia (Fig. 1). Further, Drosophila oogenesis is amenableto genetic analysis, making it an attractive model for identify-ing molecules involved in epithelium formation. In this reportwe present the molecular and functional characterization of thegene egghead (egh), which encodes a novel molecule that islikely to be crucial for the adhesion of the follicular epitheliumto germ cells throughout oogenesis.In both invertebrates and vertebrates, cell adhesionmolecules have been shown to play an essential role in epi-thelial organization (reviewed by Gumbiner et al., 1992). Forexample, in vertebrates and Drosophila, E-cadherin celladhesion molecules are required for the formation and main-tenance of epithelial structure, particularly in epithelia under-going complex morphogenetic rearrangements (reviewed byTakeichi, 1995; Tepass et al., 1996; Uemura et al., 1996). Keymediators of cadherin function are cytoplasmic α- and β-catenin, which bind to both the cytoplasmic domain ofcadherins and to f-actin filaments, providing a crucial linkbetween adhesion and regulation of cell shapes andmovements.3863Development 122, 3863-3879 (1996)Printed in Great Britain © The Company of Biologists Limited 1996DEV8357Notch (N) and other neurogenic genes have been implicatedin two fundamental processes, lateral specification of cellfates, and epithelial development. Previous studies havesuggested that the neurogenic gene brainiac (brn) is specif-ically required for epithelial development (Goode, S.,Morgan, M., Liang, Y-P. and Mahowald, A. P. (1996). Dev.Biol. 178, 35-50). In this report we show that egghead (egh),a gene with phenotypes identical to brn, encodes for a novel,putative secreted or transmembrane protein. We describethe role of egh and brn germline function in the morpho-genesis of the follicular epithelium from the time it is bornthrough the time that it migrates towards the oocyte late inoogenesis.By comparing the function of germline egh and brn to Nduring oogenesis, we have obtained direct evidence for theinvolvement of Notch in maintenance of the follicle cellepithelium, and the specificity of brn and egh in epithelialdevelopment during oogenesis. The most strikingphenotype observed for all three genes is a loss of apical-basal polarity and accumulation of follicular epithelial cellsin multiple layers around the oocyte. The spatiotemporalonset of this adenoma-like phenotype correlates with thedifferential accumulation of egh transcripts in the oocyteat stage 4 of oogenesis. In contrast to N, we find that brnand egh are essential for the organization, but not specifi-cation, of stalk and polar cells.The expression patterns and functional requirements ofbrn, egh, and N lead us to propose that these genes mediatefollicular morphogenesis by regulating germline-folliclecell adhesion. This proposal offers explanations for (1) theinvolvement of egh and brn in N-mediated epithelial devel-opment, but not lateral specification, (2) why brn and eghembryonic neurogenic phenotypes are not as severe as Nphenotypes, and (3) how egh and brn influence Egfr-mediated processes. The correlation between the differen-tial expression of egh in the oocyte and the differentialrequirement for brn, egh, and N in maintaining the follic-ular epithelium around the oocyte, suggests that Eggheadis a critical component of a differential oocyte-follicle celladhesive system.Key words: Notch, epithelium, cell interaction, morphogenesis,neurogenic genes, oogenesis, signaling pathway, DrosophilaSUMMARYThe neurogenic genes egghead and brainiacdefine a novel signaling pathwayessential for epithelial morphogenesis during DrosophilaoogenesisScott Goode1,§, Michael Melnick1,*, Tze-Bin Chou1,†and Norbert Perrimon21Department of Genetics, and 2Howard Hughes Medical Institute, Harvard Medical School, 200 Longwood Avenue, Boston,Massachusetts 02115, USA*Present address: Laboratory of Cell Signaling, New England BioLabs, 32 Tozer Road, Beverly, MA 01915, USA†Present address: Department of Zoology, National Taiwan University, Taipei, Taiwan, Republic of China§Address correspondence to Scott Goode by e-mail: [email protected] second class of cell surface factors essential for epithelialdevelopment are receptor tyrosine kinases and their ligands.For example, vertebrate hepatocyte growth factor and p190METreceptor tyrosine kinase induce chemotactic migration, prolif-eration, and differentiation of epithelial cells, and elicit epi-thelial tubule morphogenesis (Naldini et al., 1991). Epidermalgrowth factor receptor (Egfr) mutant mice suffer from multi-organ failure due to widespread impairment of epithelial devel-opment (Miettinen et al., 1995), and mice with reduced levelsof one Egfr ligand, transforming growth factor α (TGFα),share some of these developmental abnormalities (Luetteke etal., 1993; Mann et al., 1993). Egfr and grk TGFα mutantDrosophila show similar abnormalities. Disruption of Egfr infollicle cells or TGFα signals in germ cells results in loss ofdorsal-ventral patterned array of follicle cell shapes andimpaired development of the follicular epithelium (Schüpbach,1987; Goode et al., 1996). The discontinuities of the monolayerfollicular epithelium observed in TGFα or Egfr mutantDrosophila are reminiscent of the extreme thinning observedin stratified epithelia of newborn Egfr mutant mice (Goode etal., 1996; Miettinen et al., 1995).A third class of molecules essential for epithelial developmentare encoded by the neurogenic genes. Although intensivelystudied for their function in lateral specification (reviewed byArtavanis-Tsakonas et al., 1995), the Drosophila neurogenicgenes Notch (N),