Receptor tyrosine kinase (RTK) signaling plays an instructive role in cell fate decisions, whereas Notch signaling is often involved in restricting cellular competence for differentiation. Genetic interactions between these two evolutionarily conserved pathways have been extensively documented. The underlying molecular mechanisms, however, are not well understood. Here, we show that Yan, an Ets transcriptional repressor that blocks cellular potential for specification and differentiation, is a target of Notch signaling during Drosophila eye development. The Suppressor of Hairless (Su[H]) protein of the Notch pathway is required for activating yan expression, and Su(H) binds directly to an eye-specific yan enhancer in vitro. In contrast, yan expression is repressed by Pointed (Pnt), which is a key component of the RTK pathway. Pnt binds specifically to the yan enhancer and competes with Su(H) for DNA binding. This competition illustrates a potential mechanism for RTK and Notch signals to oppose each other. Thus, yan serves as a common target of Notch/Su(H) and RTK/Pointed signaling pathways during cell fate specification.

Fetchko M, Huang W, Li Y, Lai ZC.   Drosophila Gp150 is required for early ommatidial development through modulation of Notch signaling. EMBO J 2002 Mar 1;21(5):1074-83

Cellular signaling activities must be tightly regulated for proper cell fate control and tissue morphogenesis. Here we report that the Drosophila leucine-rich repeat transmembrane glycoprotein Gp150 is required for viability, fertility and development of the eye, wing and sensory organs. In the eye, Gp150 plays a critical role in regulating early ommatidial formation. Gp150 is highly expressed in cells of the morphogenetic furrow (MF) region, where it accumulates exclusively in intracellular vesicles in an endocytosis-independent manner. Loss of gp150 function causes defects in the refinement of photoreceptor R8 cells and recruitment of other cells, which leads to the formation of aberrant ommatidia. Genetic analyses suggest that Gp150 functions to modulate Notch signaling. Consistent with this notion, Gp150 is co-localized with Delta in intracellular vesicles in cells within the MF region and loss of gp150 function causes accumulation of intracellular Delta protein. Therefore, Gp150 might function in intracellular vesicles to modulate Delta-Notch signaling for cell fate control and tissue morphogenesis.

Dhulkotia D, Nguyen D, Lai ZC.   Evolutionary conservation of the leucine-rich repeat transmembrane protein Gp150 in Drosophila and Bombyx. Dev Genes Evol 2000 Mar;210(3):145-50

Gp150 is a transmembrane glycoprotein belonging to the leucine-rich repeat (LRR) superfamily. Here we report the molecular characterization of a Gp150 homolog in Drosophila virilis, which is separated from Drosophila melanogaster by about 60 million years. A silkworm Bombyx mori Gp150 homolog was identified through a sequence database search. Sequence analysis revealed high conservation in the LRRs and cysteine motifs flanking the LRR region in the extracellular domain of Gp150. Using an in vivo assay, we demonstrated that the extracellular domain is essential for Gp150 function. Moreover, structural features unique to the Gp150 proteins were identified that include an incomplete carboxy-flanking cysteine motif, acidic regions on both sides of the LRR region in the extracellular domain, and a short cytoplasmic domain with three putative tyrosine hosphorylation motifs, which might be involved in interaction with SH2 domains. Thus, Gp150 defines a new subfamily of LRR proteins and may be involved in signal transduction. Sequence comparison of the two Drosophila gp150 genes demonstrated a high degree of conservation of genome organization downstream of the gp150 gene. Interestingly, D. virilis gp150 coding region appears to have an additional intron, an uncommon feature in homologs of other genes. The expression pattern of gp150 during  embryogenesis in D. melanogaster and D. virilis was found to be identical. gp150 transcripts were localized generally to regions where cells are undergoing dramatic morphogenetic movements. This is further corroborated by the localization of gp150 transcripts in eye imaginal discs in the region spanning the morphogenetic furrow.

Nguyen DN, Rohrbaugh M, Lai Z.   The Drosophila homolog of Onecut homeodomain proteins is a neural-specific transcriptional activator with a potential role in regulating neural differentiation. Mech Dev 2000 Oct;97(1-2):57-72

We report here the characterization of the Drosophila homolog of the onecut homeobox gene, which encodes a protein product with one cut domain and one homeodomain. We present evidence that D-Onecut can bind to similar DNA sequences with high specificity and affinity as other Onecut proteins through the highly conserved cut domain and homeodomain. Interestingly, the cut domain alone can mediate DNA-binding, but the homeodomain cannot. However, depending upon the promoter context, we observed cooperative interactions between the two domains to confer high DNA-binding affinity and specificity. D-Onecut appears to be a moderate transcriptional activator and functions as a nuclear protein in neuronal tissues of both the CNS and PNS during development and in the adult. In the eye, D-Onecut expression is independent of glass, a transcriptional regulator of R cell differentiation. Taken together, our results suggest a role for D-Onecut in the regulation of some aspects of neural differentiation or maintenance. In support of this notion, overexpression of a putative dominant negative form of D-Onecut during eye development does not affect early cell fate specification, but severely affects photoreceptor differentiation.

Wen Y, Nguyen D, Li Y, Lai ZC.   The N-terminal BTB/POZ domain and C-terminal sequences are essential for Tramtrack69 to specify cell fate in the developing Drosophila eye. Genetics 2000 Sep;156(1):195-203

Lai ZC, Li Y.   Tramtrack69 is positively and autonomously required for Drosophila photoreceptor development. Genetics 1999 May;152(1):299-305

Price MD, Lai Z.   The yan gene is highly conserved in Drosophila and its expression suggests a complex role throughout development. Dev Genes Evol 1999 Apr;209(4):207-17

van Huizen R, Miller K, Chen DM, Li Y, Lai ZC, Raab RW, Stark WS, Shortridge RD, Li M.   Two distantly positioned PDZ domains mediate multivalent INAD-phospholipase C interactions essential for G protein-coupled signaling. EMBO J 1998 Apr 15;17(8):2285-97

Lai ZC, Fetchko M, Li Y.   Repression of Drosophila photoreceptor cell fate through cooperative action of two transcriptional repressors Yan and Tramtrack. Genetics 1997 Nov;147(3):1131-7

Li S, Li Y, Carthew RW, Lai ZC.   Photoreceptor cell differentiation requires regulated proteolysis of the transcriptional repressor Tramtrack. Cell 1997 Aug 8;90(3):469-78

Balczarek KA, Lai ZC, Kumar S.   Evolution of functional diversification of the paired box (Pax) DNA-binding domains. Mol Biol Evol 1997 Aug;14(8):829-42

Lai ZC, Harrison SD, Karim F, Li Y, Rubin GM.   Loss of tramtrack gene activity results in ectopic R7 cell formation, even in a sina mutant background. Proc Natl Acad Sci U S A 1996 May 14;93(10):5025-30

Kumar S, Balczarek KA, Lai ZC.   Evolution of the hedgehog gene family. Genetics 1996 Mar;142(3):965-72

Treisman JE, Lai ZC, Rubin GM.   Shortsighted acts in the decapentaplegic pathway in Drosophila eye development and has homology to a mouse TGF-beta-responsive gene. Development 1995 Sep;121(9):2835-45

Lai ZC, Rushton E, Bate M, Rubin GM.   Loss of function of the Drosophila zfh-1 gene results in abnormal development of mesodermally derived tissues. Proc Natl Acad Sci U S A 1993 May 1;90(9):4122-6

Lai ZC, Rubin GM.   Negative control of photoreceptor development in Drosophila by the product of the yan gene, an ETS domain protein. Cell 1992 Aug 21;70(4):609-20

Lai ZC, Fortini ME, Rubin GM.   The embryonic expression patterns of zfh-1 and zfh-2, two Drosophila genes encoding novel zinc-finger homeodomain proteins. Mech Dev 1991 Jun;34(2-3):123-34

Fortini ME, Lai ZC, Rubin GM.   The Drosophila zfh-1 and zfh-2 genes encode novel proteins containing both zinc-finger and homeodomain motifs. Mech Dev 1991 Jun;34(2-3):113-22