Molecular mechanism of cyclic Notch signalling

Research

The first sign of segmentation is seen when vertebrate embryos develop transient structures called somites, which are the embryonic precursors of muscles, dermis and bones. As development proceeds, the embryo makes new somites according to a strict periodic schedule controlled by a molecular clock. Interference with the proper function of this process will consequently lead to the formation of abnormal embryonic structures that will later give rise to animals with severe morphological segmentation defects. Recent studies have implicated the Notch cell-cell signalling pathway as a key component of the machinery of the segmentation clock. However, the information available concerning the regulation of this mechanism is very limited, almost non-existent.

The aim of the laboratory is to enhance our knowledge of the molecular mechanism of cyclic Notch signalling implicated in the machinery of the segmentation clock. We want to understand the mechanism by which cyclic Notch activity is modified, with respect to the canonical Notch pathway, to control periodic gene activation. In particular, we are interested in the function of Lunatic fringe, an enzyme able to modify the Notch receptor and the function of Nrarp, a Notch downstream target gene, and their implication in the regulation of oscillating Notch activity. We are also interested in the characterisation of the role of the Notch signalling pathway in early muscle patterning and differentiation.

Publications

1.  Terry AJ, Sturrock M, Dale JK, Maroto M, Chaplain M (2011). A spatio-temporal model of Notch signalling in the zebrafish segmentation clock: conditions for synchronised oscillatory dynamics. PLoS ONE 6(2):e16980

2. Gibb S, Maroto M, Dale JK (2010). Segmentation clock comprehension moves up a Notch. Trends Cell Biol 20(10):593-600

 3. Tenin G, Wright D, Ferjentsik Z, Bone R, McGrew MJ, MarotoM (2010).The chick somitogenesis oscillator is arrested before all paraxial mesoderm is segmented into somites. BMC Dev Biol 10:24

 4. Wright D, FerjentsikZ, Qiu X, Jiang YJ, Van Hateren N, Wilson SA, Malapert P, Pourquie O, Dale JK, Maroto M (2009). Cyclic Nrarp mRNA expression is regulated by the somitic oscillator but Nrarp protein levels do not oscillate. Dev Dyn238:3043-3055

 5. Ferjentsik Z, Hayashi S, Dale JK, Bessho Y, Herreman A, De Strooper B, del Monte G, de la Pompa JL, Maroto M (2009). Notch is a critical component of the mouse somitogenesis oscillator and is essential for the formation of the somites. PLoS Genetics 5(9):e1000662

 6. Hayashi S, Shimoda T, Nakajima M, , Tsukada Y, Sakumura Y, Dale JK, Maroto M, Kohno K, Matsui T, Bessho Y (2009). Sprouty4, an FGF inhibitor, displays cyclic gene expression under the control of theNotch segmentation clock in the mouse PSM. PLoS ONE4(5):e5603

 7. Gibb S, Zagorska A, Melton K, Tenin G, Trainor P, Maroto M*, Dale JK*(2009). Interfering with Wnt Signalling alters the Periodicity of the Segmentation Clock. Dev Biol330(1):21-31. 

 8. Palmeirim I, Rodrigues S, Dale JK, Maroto M (2008). Development on time.  Adv Exp Med Biol 641:62-71.

9. Maroto M, Iimura T, Dale JK, Bessho Y (2008). BHLH proteins and their role in somitogenesis.  Adv Exp Med Biol (2008) 638:124-139.

10. Shan SW, Tang MK, Chow Ph, Maroto M, Cai DQ, Lee KKH (2007). Induction of growth arrest and polycomb genes expression by reversine allows C2C12 cells to be reprogrammed to various differentiated cell types. Proteomics 7:4303-4316.

11. Dale JK, Malapert P, Chal J, Vilhais-Neto G, Maroto M, Johson T, Jayasinghe S, Trainor P, Herrmann B, Pourquie O (2006). Oscillations of the Snail genes in the presomitic mesoderm coordinate segmental patterning and morphogenesis in vertebrate somitogenesis. Dev. Cell10:355-366

 12. Maroto M, Dale JK, Dequeant ML, Petit AC, Pourquie O (2005). Synchronized cycling gene oscillations in PSM cells require cell-cell contact. Intr. J. Dev. Biol.49:309-315

13. Dale JK, Maroto M (2003). A Hes1-based oscillator in cultured cells and its potential implications for the Segmentation clock. BioEssays25(3):200-203

14.  Dale JK*, Maroto M*, DequeantML, MalapertP, McGrew M, PourquieO (2003). Periodic Notch inhibition by Lunatic Fringe underlies the chick Segmentation Clock. Nature 421:275-278

15.  Maroto M, Pourquie O (2001). A molecular clock involved in somite segmentation. Curr Top Dev Biol. Vol. 51:221-248

16.  Pourquie O, Dale JK, Dubrulle J, Jouve C, Maroto M, McGrew M (2001). A molecular clock linked to vertebrate segmentation. In “The Origin and Fate of Somites”. E.J. Sanders et al. (Eds). IOS Press.

17. Arredondo J, Ferreres RM, Maroto M, Cripps R, Marco R, Bernstein SI, Cervera M (2001). Control of Drosophila paramyosin/miniparamyosin gene expression differential regulatory mechanisms for muscle-specific transcription. J. Biol. Chem. 276:8278-8287

18.  Domingo A, Gonzalez-Jurado J, Maroto M, Diaz C, Vinos J, Carrasco C, Cervera M, Marco R (1998). Troponin-T is a calcium-binding protein in insect muscle: in vivo phosphorylation, muscle-specific isoforms and developmental profile in Drosophila melanogaster. J. Muscle Res. Cell Motil. 19:393-403

19.  Reshef R, Maroto M, Lassar AB (1998). Regulation of dorsal somitic cell fates: BMPs and noggin control the timing and pattern of myogenic regulator expression. Genes Dev. 12:290-303

20.  Maroto M, Reshef R, Munsterberg A, Koester S, Goulding M, Lassar AB (1997). Ectopic Pax-3 activates MyoD and Myf-5 expresssion in embryonic mesoderm and neural tissue. Cell 89:139-148

21.  Maroto M, Arredondo JJ, Goulding D, Marco R, Bullard B, Cervera M (1996). Drosophila paramyosin/miniparamyosin gene products show a large diversity in quantity, localization, and isoform pattern: a possible role in muscle maturation and function. J. Cell Biol.134:81-92

22. Maroto M, Arredondo JJ, San Roman M, Marco R, Cervera M (1995). Analysis of the paramyosin/miniparamyosin gene complex: Miniparamyosin is an independently transcribed, distinct paramyosin isoform, widely distributed in invertebrates. J. Biol. Chem. 270:4375-4382

23. Medina FJ, Cerdido A, Maroto M, Manzanares M, Marco R (1994). Enhancement of the immunochemical detection of antigens by microwave irradiation. Benefits and limitations studied in isolated plant nuclei and Drosophila embryos in toto. Histochemistry 102:45-50

24. Marco R, de Juan E, Ushakov I, Hernandorena A, Gonzalez-Jurado J, Calleja M, Manzanares M, Maroto M, Garesse R, Reitz G, Miquel J (1994). Arthropod model systems for studying complex biological processes in the space environment. Adv. Space Res.14 (8):215-227

25.  Marco R, Gonzalez-Jurado J, Calleja M, Garesse R, Maroto M, Ramirez E, Holgado MC, De Juan, Miquel J (1992). Microgravity effects on Drosophila melanogaster development and aging: Comparative analysis of the results of fly experiment in the Biokosmos IX URSS Biosatellite flight. Adv. Space Res. 12 (1):157-166

26.  Vinos J, Maroto M, Garesse R, Marco R, Cervera M (1992). Drosophila melanogasterparamyosin: Developmental pattern, mapping and properties deduced from its complete coding sequence. Mol. Gen. Genet. 231:385-394

27.  Maroto M, Vinos J, Marco R, Cervera M (1992). Autophosphorylating protein kinase activity in titin-like arthropod projectin. J. Mol. Biol. 224:287-291