Hindsight mediates the role of notch in suppressing hedgehog signaling and cell proliferation.

Temporal and spatial regulation of proliferation and differentiation by signaling pathways is essential for animal development. Drosophila follicular epithelial cells provide an excellent model system for the study of temporal regulation of cell proliferation. In follicle cells, the Notch pathway stops proliferation and promotes a switch from the mitotic cycle to the endocycle. Here, we show that zinc-finger transcription factor Hindsight mediates the role of Notch in regulating cell differentiation and the switch of cell-cycle programs. Hindsight is required and sufficient to stop proliferation and induce the transition to the endocycle. To do so, it represses string, Cut, and Hedgehog signaling, which promote proliferation during early oogenesis. Hindsight, along with another zinc-finger protein, Tramtrack, downregulates Hedgehog signaling through transcriptional repression of cubitus interruptus. Our studies suggest that Hindsight bridges the two antagonistic pathways, Notch and Hedgehog, in the temporal regulation of follicle-cell proliferation and differentiation.

[1]  David Stein,et al.  Drosophila dMyc is required for ovary cell growth and endoreplication , 2004, Development.

[2]  Y. Nibu,et al.  Finb, a multiple zinc finger protein, represses transcription of the human angiotensinogen gene. , 2004, International journal of molecular medicine.

[3]  Antonio Baonza,et al.  Control of cell proliferation in the Drosophila eye by Notch signaling. , 2005, Developmental cell.

[4]  D. Kalderon,et al.  Regulation of cell proliferation and patterning in Drosophila oogenesis by Hedgehog signaling. , 2000, Development.

[5]  Hannele Ruohola-Baker,et al.  Notch-Dependent Fizzy-Related/Hec1/Cdh1 Expression Is Required for the Mitotic-to-Endocycle Transition in Drosophila Follicle Cells , 2004, Current Biology.

[6]  H. Lipshitz,et al.  Control of photoreceptor cell morphology, planar polarity and epithelial integrity during Drosophila eye development. , 2002, Development.

[7]  C. K. Motzny,et al.  The Drosophila cubitus interruptus protein and its role in the wingless and hedgehog signal transduction pathways , 1995, Mechanisms of Development.

[8]  Hannele Ruohola-Baker,et al.  Notch signaling through Tramtrack bypasses the mitosis promoting activity of the JNK pathway in the mitotic-to-endocycle transition of Drosophila follicle cells , 2006, BMC Developmental Biology.

[9]  T. Kornberg,et al.  Proteolysis That Is Inhibited by Hedgehog Targets Cubitus interruptus Protein to the Nucleus and Converts It to a Repressor , 1997, Cell.

[10]  Iva Greenwald,et al.  Presenilin is required for activity and nuclear access of Notch in Drosophila , 1999, Nature.

[11]  D. Montell,et al.  Eyes Absent, a key repressor of polar cell fate during Drosophila oogenesis , 2002, Development.

[12]  S. Bray.  Notch signalling: a simple pathway becomes complex , 2006, Nature Reviews Molecular Cell Biology.

[13]  Douglas R Lowy,et al.  p16INK4a gene promoter variation and differential binding of a repressor, the ras-responsive zinc-finger transcription factor, RREB , 2003, Oncogene.

[14]  A. Spradling,et al.  Cell cycle control of chorion gene amplification. , 1998, Genes & development.

[15]  H. Johnston,et al.  Delta signaling from the germ line controls the proliferation and differentiation of the somatic follicle cells during Drosophila oogenesis , 2001 .

[16]  C. Lehner,et al.  Drosophila fizzy-related Down-Regulates Mitotic Cyclins and Is Required for Cell Proliferation Arrest and Entry into Endocycles , 1997, Cell.

[17]  H. Edenberg,et al.  A human Raf-responsive zinc-finger protein that binds to divergent sequences. , 1999, Nucleic acids research.

[18]  H. Lipshitz,et al.  Control of germ-band retraction in Drosophila by the zinc-finger protein HINDSIGHT. , 1997, Development.

[19]  J. I. Horabin,et al.  A positive role for Patched in Hedgehog signaling revealed by the intracellular trafficking of Sex-lethal, the Drosophila sex determination master switch , 2003, Development.

[20]  Lawrence Lum,et al.  The Hedgehog Response Network: Sensors, Switches, and Routers , 2004, Science.

[21]  P. Ingham,et al.  hedgehog is required for the proliferation and specification of ovarian somatic cells prior to egg chamber formation in Drosophila. , 1996, Development.

[22]  H. Lipshitz,et al.  Downregulation of Jun kinase signaling in the amnioserosa is essential for dorsal closure of the Drosophila embryo , 2001, Current Biology.

[23]  H. Ruohola-Baker,et al.  Notch-Delta signaling induces a transition from mitotic cell cycle to endocycle in Drosophila follicle cells. , 2001, Development.

[24]  S. Bray,et al.  Notch signalling mediates segmentation of the Drosophila leg. , 1998, Development.

[25]  P. O’Farrell,et al.  Fluctuations in Cyclin E levels are required for multiple rounds of endocycle S phase in Drosophila , 1998, Current Biology.

[26]  D. Kalderon,et al.  Proteolysis of cubitus interruptus in Drosophila requires phosphorylation by protein kinase A. , 1999, Development.

[27]  J. S. Britton,et al.  Cis-regulatory elements of the mitotic regulator, string/Cdc25. , 1999, Development.

[28]  P. Ingham,et al.  The role of segment polarity genes during early oogenesis in Drosophila. , 1996, Development.

[29]  C. Montell,et al.  tramtrack is a transcriptional repressor required for cell fate determination in the Drosophila eye. , 1993, Genes & development.

[30]  Tien-chi Pan,et al.  Analysis of cell migration using whole-genome expression profiling of migratory cells in the Drosophila ovary. , 2006, Developmental cell.

[31]  N. Baker,et al.  Extracellular signals responsible for spatially regulated proliferation in the differentiating Drosophila eye. , 2005, Developmental cell.

[32]  G. Struhl,et al.  Nuclear Access and Action of Notch In Vivo , 1998, Cell.

[33]  D. Montell,et al.  Spatially localized Kuzbanian required for specific activation of Notch during border cell migration. , 2007, Developmental biology.

[34]  Wu-Min Deng,et al.  Notch-dependent downregulation of the homeodomain gene cut is required for the mitotic cycle/endocycle switch and cell differentiation in Drosophila follicle cells , 2005, Development.