G
protein-coupled receptors (GPCRs)
[ JM Boeynaems, David Communi, Didier Communi, S.Costagliola , C.Ledent, F.Libert, M.Parmentier, I.Pirson, B.Robaye, G.Vassart]
After having
pioneered the cloning by homology of rhodopsin-like GPCRs, the Institute has
built expertise in the study of a variety of GPCR subfamilies. These include
mainly the glycoprotein hormone receptors, receptors for chemokines and other
leucocyte chemoattractants, adenosine receptors, P2Y nucleotide receptors,
cannabinoid receptors and neuropeptide receptors. Current studies concentrate
on structure-function relationships, regulation of downstream regulatory
cascades and gene expression by microarrays, in vivo phenotypic studies of mice
with invalidated receptor genes, role of GPCRs in tumorigenesis, role of homo-
and hetero-dimerization of GPCRs. A strong emphasis is put on the
identification of the natural agonists of a diversity of orphan GPCRs
Main recent publications
Blanpain C, Vanderwinden JM,
Cihak J, Wittamer V, Le Poul E, Issafras H, Stangassinger M, Vassart G,
Marullo S, Schlondorff D, Parmentier M, Mack M.
Multiple active states and
oligomerization of CCR5 revealed by functional properties of monoclonal
antibodies.
Mol. Biol. Cell. 13:723-37 ( 2002).
Costagliola S, Panneels V,
Bonomi M, Koch J, Many MC, Smits G, Vassart G.
Tyrosine sulfation is
required for agonist recognition by glycoprotein hormone receptors.
EMBO J. 21:504-13 (2002).
Vlaeminck-Guillem V, Ho SC,
Rodien P, Vassart G, Costagliola S.
Activation of the cAMP
Pathway by the TSH Receptor Involves Switching of the Ectodomain from a
Tethered Inverse Agonist to an Agonist.
Mol.Endocrinol. 16:736-46 (2002).
Robaye B, Ghanem E,
Wilkin F, Fokan D, Van Driessche W, Schurmans S, Boeynaems J-M, Beauwens R
Loss of nucleotide
regulation of epithelial chloride transport in the jejunum of P2Y 4 -null mice
Mol Pharmacol, 63:777-783 (2003).
Smits G, Olatunbosun O,
Delbaere A, Pierson R, Vassart G, Costagliola S.
Ovarian hyperstimulation
syndrome due to a mutation in the follicle-stimulating hormone receptor.
New England Journal of Medicine 349:760-6 (2003).
Smits G, Campillo M,
Govaerts C, Janssens V, Richter C, Vassart G, Pardo L, Costagliola S.
Glycoprotein hormone
receptors: determinants in leucine-rich repeats responsible for ligand
specificity.
EMBO J 22:2692-703 (2003).
Wittamer V, Franssen JD,
Vulcano M, Mirjolet JF, Le Poul E, Migeotte I, Brezillon S, Tyldesley R,
Blanpain C, Detheux M, Mantovani A, Sozzani S, Vassart G, Parmentier M,
Communi D.
Specific Recruitment of
Antigen-presenting Cells by Chemerin, a Novel Processed Ligand from Human
Inflammatory Fluids.
J.Exp.Med. 198:977-85 (2003).
Vassart G, Pardo L,
Costagliola S.
A molecular dissection of the glycoprotein
hormone receptors.
Trends Biochem.Sci. 29:119-26 (2004).
Marteau F, Suarez Gonzalez
N, Communi D, Goldman M, Boeynaems J-M, Communi D.
Thrombospondin-1 and
indoleamine 2,3-dioxygenase are major targets of extracellular ATP in human
dendritic cells
Blood, 106 :3860-3866 (2005).
Ledent C, Demeestere I, Blum
D, Petermans J, Hamalainen T, Smits G, Vassart G.
Premature ovarian aging in
mice deficient for Gpr3.
Proc.Natl.Acad.Sci.U.S A 102:8922-6 (2005).
Migeotte I, Riboldi E,
Franssen JD, Gregoire F, Loison C, Wittamer V, Detheux M, Robberecht P,
Costagliola S, Vassart G, Sozzani S, Parmentier M, Communi D.
Identification and
characterization of an endogenous chemotactic ligand specific for FPRL2
J Exp Med. 201:83-93 (2005).
Urizar E, Montanelli L, Loy
T, Bonomi M, Swillens S, Gales C, Bouvier M, Smits G, Vassart G, Costagliola
S.
Glycoprotein hormone
receptors: link between receptor homodimerization and negative cooperativity.
EMBO J. 24:1954-64 (2005).
Laurent P, Becker JAJ,
Valverde O, Ledent C, de Kerchove d’Exaerde A, Schiffmann SN, Maldonado R,
Vassart G and Parmentier M.
The prolactin-releasing
peptide acts as a functional antagonist of the opioid system through its
receptor GPR10.
Nature Neurosciences, 8:1735-1741 (2005).
El-Asmar L, Springael JY,
Ballet S, Urizar Andrieu E, Vassart G, Parmentier M.
Evidence for negative
binding cooperativity within CCR5-CCR2b heterodimers.
Mol Pharmacol. 67:460-469 (2005).
Bar
I, Guns
PJ, Metallo
J, Cammarata
D, Wilkin
F, Boeynams
JM, Bult
H, Robaye
B.
Knockout mice reveal a role for P2Y6 receptor in macrophages,
endothelial cells, and vascular smooth muscle cells.
Mol Pharmacol.
2008;74(3):777-84. |
Stem cells, development and cancer. 
[ Cédric Blanpain , Alexandra Van
Keymeulen ]
Our group is studying
- The cellular and molecular mechanisms regulating cell fate specification during embryonic development and tissue homeostasis.
During
embryonic development, undifferentiated progenitors cells are
progressively specified to adopt a particular cell fate. To dissect the
molecular mechanisms involved in cell fate specification, we are
studying the differentiation
of embryonic stem cells in-vitro. Embryonic stem cells present the
great advantage to be easily genetically modified and their in-vitro
differentiation recapitulates relatively well normal embryonic development.
We are studying cardiac specification as a model because the heart is
the first organ to develop during embryogenesis, cardiac
differentiation is induced by a robust and well-characterized key
regulator genes conserved from Drosophila to human, and present important clinical implications.
- The role of adult stem cells during cancer initiation.
Cancer
is the result of a multi-step process requiring the accumulation of
mutations in several genes. For most cancers, the target cells of
oncogenic mutations are unknown. Adult stem cells (SCs) might be the
initial target
cells as they self-renew for extended periods of time, providing
increased opportunity to accumulate the mutations required for cancer
formation. However, for most cancer it is still unknown whether the
initial oncogenic
mutations arise in adult stem cells or in more committed cells that
re-acquire stem cell-like properties. We are determining whether
epithelial SCs are the initial target cells of oncogenic mutations
during cancer
formation and represent the natural niche for pre-cancerous cells.
Using mice genetics, we are also exploring the influence of the
pre-existing self-renewing capacity of adult SC during cancer formation.
- The role of cancer stem cells during cancer growth and relapse after therapy.
Recent
studies provide compelling evidence that certain leukemia and human
solid tumors contain cells with high clonogenic potential, capable of
reforming parental tumor upon transplantation, and which have been referred
to as cancer stem cells (CSC). However, it remains unclear whether all
cancers contain CSCs and how do CSCs contribute to the actual tumor
growth. We are using in this project different approaches combining cell
isolation and transplantation as well as unbiased genetic approach to
determine the contribution of CSC during cancer growth and relapse
after therapy of different epithelial cancers.
Main recent publications
Blanpain C, Lowry WE, Geoghegan A, Polak L, Fuchs E.
Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche.
Cell. 2004 118(5):635-48. Featured article accompanied by a preview.
Blanpain C, Lowry WE, Pasolli A, and Fuchs E.
Canonical notch signaling functions as a commitment switch in the epidermal lineage.
Genes Dev. 2006, 20:3022-35. Cover article.
Lowry, WE.*, Blanpain C.*, Nowak JA., Guasch G., Lewis L. and Fuchs E. *
denotes co-first author. Defining the impact of b-catenin/Tcf transactivation on epithelial stem cells.
Genes Dev. 2005 (13):1596-611. Cover article.
Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M, Fuchs E.
Defining the epithelial stem cell niche in skin.
Science. 2004 303:359-63.
Blanpain C, Horsley V, Fuchs E.
Epithelial Stem Cells: Turning over New Leaves.
Cell. 2007, 128:445-58.
Blanpain C, Fuchs E.
Epidermal stem cells of the skin.
Annu Rev Cell Dev Biol. 2006; 22:339-73.
Blanpain C, Fuchs E.
p63: revving up epithelial stem-cell potential.
Nat Cell Biol. 2007 (7):731-3. |
Metabolism of
phosphoinositides
[ David Communi, C.Erneux, I.Pirson, S.Schurmans ]
Since 1985, our work at the
Institute has consisted in the definition at the molecular level of the
mechanisms and enzymes involved in the signal termination reaction of new
important intracellular molecules. The defined mechanisms, the cloning of new
enzymes such as InsP3 3-kinases, 5-phosphatases, SHIP1 and SHIP2 have
introduced new concepts and new targets in pharmacology. Loss of SHIP2 in mice
leads to increased sensitivity to insulin.
Main recent publications
Giuriato S., Pesesse X.,
Bodin S., Sasaki T., Viala C., Marion E., Penninger J., Schurmans S., Erneux
C., and Payrastre B.
SH2 domain containing
inositol 5-phosphatases 1 and 2 in blood platelets: interaction and
respective role in the control of phosphatidylinositol 3,4,5-trisphosphate
level.
Biochem J., 376:199-207 (2003).
Pouillon V.,
Hascakova-Bartova R., Pajak B., Adam E., Bex F., Dewaste V., Van Lint C., Leo
O., Erneux C., and Schurmans S.
Inositol
1,3,4,5-tetrakisphosphate is essential for normal T lymphocyte development.
Nature Immunol., 4:1136-1143 (2003).
Schurmans S.
Ship2 and insulin
sensitivity: a role in type 2 diabetes?
Bull. Mem. Acad. R. Med. Belg., 158: 335-9 (2003).
Kaisaki P.J., Delépine M.,
Woon P. Y., Sebag-Montefiore L., Wilder S.P., Menzel S., Vionnet N., Marion
E., Riveline J.P., Charpentier G., Schurmans S., Levy J.C., Lathrop M.,
Farrall M., and Gauguier D.
Polymorphisms in Type-II SH2
domain-containing Inositol 5-Phosphatase (INPPL1, SHIP2) are Associated with
Physiological Abnormalities of the Metabolic Syndrome.
Diabetes 53: 1900-1904 (2003).
Hascakova-Bartova R.,
Pouillon V., Dewaste V., Moreau C., Jacques C., Banting G., Schurmans S., and
Erneux C.
Identification and
subcellular distribution of endogenous Ins(1,4,5)P3 3-kinase B in mouse
tissues.
Biochem. Biophys. Res. Commun., 323: 920-925 (2003).
Wang Y., Keogh R. J., Hunter
M. G., Mitchell C. A., Frey R. S., Javaid K., Malik A. B., Schurmans S.,
Tridandapani S., and Marsh C. B.
SHIP2 is recruited to the
cell membrane upon M-CSF stimulation and regulates M-CSF-induced signaling.
J. Immunol. 173: 6820-6830 (2003).
Jacobs C., Onnockx S,
Vandenbroere I. and Pirson I.
Endogenous SHIP2 does not
localize in lipid rafts in 3T3-L1 adipocytes.
FEBS Letters 565: 70-74 (2004).
Paternotte N., Zhang J.,
Vandenbroere I., Backers K., Blero D., Kioka N., Vanderwinden J-M, Pirson I.,
and Erneux C.
SHIP2 interaction with the
cytoskeletal protein Vinexin.
FEBS Journal 272: 6052-6066 (2005).
Blero D., Zhang J., Pesesse
X., Payrastre B., Dumont J.E., Schurmans S., and Erneux C.
Phosphatidylinositol
3,4,5-trisphosphate modulation in Ship2-deficient mouse embryonic
fibroblasts.
FEBS J., 272: 2512-2522 (2005).
Poinas, A., Backers,
K., Riley, A., Mille, S., Moreau, C., Potter, B.V.L. and Erneux,
C.
I nteraction of the catalytic domain of
Ins(1,4,5)P3 3-kinase A with inositol phosphate analogues.
BioChem Biophys Res 6:, 1449-1457 (2005).
Harada, K., Takeuchi, H., Oike,
M., Matsuda, M., Katenatsu, T., Yagisawa, H., Nakayama, K.I., Maeda, K.,
Erneux, C. and Hirata, M.
Role of PRIP-1, a novel
Ins(1,4,5)P3 binding protein in Ins(1,4,5)P3 mediated Ca2+ signaling
J Cell Physiol 202: 422-433 (2005).
Markadieu, N, Crutzen,
R, Blero, D., Erneux, C, Beauwens, R.
Hydrogen peroxide and
epidermal growth factor activate phosphatidylinositol 3-kinase and increase
sodium transport in A6 cell monolayers
Am J. Renal Physiol 288(6):F1201-12 (2005).
Vanderwinden, J.M., Wang,
D., Paternotte, N., Mignon, S., Isozaki, K. and Erneux, C.
Differences in activated
signaling pathways and in expression level of the phosphoinositides
phosphatase SHIP1 between two oncogenic mutants of the receptor tyrosine
kinase KIT
Cellular Signalling 18: 661-669 (2006).
Van Sande, J., Dequanter,
D., Massart, C., Lothaire, P., Dumont, J. E. and Erneux, C.
TSH stimulates the
generation of inositol 1,4,5-trisphosphate in human thyroid cells
J Clin Endocrinology & Metabolism 91: 1099-1107 (2006).
Vandeput, F., Backers, K.,
Villeret, V., Pesesse, X., Erneux, C.
The influence of anionic
lipids on SHIP2 phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase
activity
Cellular Signalling 18(12):2193-2199 (2006) .
Gloire, G., Charlier, E.,
Rhamouni, S., Volanti, C., Chariot, A., Erneux, C., Piette, J.
Restauration of SHIP-1
activity in human leukemic cells modify NF- B activation pathway and cellular
survival upon oxidative stress treatment
Oncogene 25(40):5485-4594 (2006).
|
Control of cell proliferation, Cancer
[ J.E. Dumont, V.
Detours ,C. Maenhaut , P. Roger, P. Heimann ]
Our group
has pioneered the study of thyroid cell proliferation and differentiation, and
has demonstrated in these cells the existence of three cascades of mitogenic
signal transduction, TSH/adenylyl cyclase/cAMP, EGF-HGF/ras/MAPK and phorbol
esters/phospholipase C/protein kinase C. The cAMP pathway promotes both
proliferation and differentiation within thyrocytes and is causatively involved
in goitrogenesis, tumor promotion and generation of hyperfunctional adenomas.
The positive regulation of thyroid cell cycle by cAMP is unique as it targets
the assembly and activation of complexes of pre-existing cyclin D and CDK4
without involving most of the intermediaries of known mitogenic signaling
cascades. Ongoing studies include the identification by molecular biology
techniques (PCR-derived methods, microarrays…) of new genes regulated by cAMP
and the investigation by proteomic approaches and two-hybrids methology of the
novel mechanisms of CDK4 activation by cAMP. Extension of this work to thyroid
tumors involves the analysis of gene expression profiles in those tissues by
the microarray technology.
Main recent publications
Heimann P, El Housni H, Ogur
G, Weterman MA, Petty EM, Vassart G.
Fusion of a novel gene,
RCC17, to the TFE3 gene in t(X ;17)(p&&.2 ;q25.3)-bearing
papillary renal cell carcinomas
Cancer
Res.61 :4130-4135 (2001).
Coulonval K, Bockstaele L,
Paternot S, Dumont JE, Roger PP.
The cyclin D3-CDK4-p27kip1
holoenzyme in thyroid epithelial cells: activation
by TSH, inhibition by TGFbeta, and phosphorylations of its subunits
demonstrated
by two-dimensional gel electrophoresis.
Exp Cell Res. 291(1):135-49 (2003).
Detours V., Wattel S., Venet
D., Hutsebaut N., Bogdanova T., Tronko M., Dumont J.E., Franc B., Thomas G.,
Maenhaut C.
Absence of a specific
radiation signature in post-Chernobyl thyroid cancers.
Br. J. Cancer 92: 1545-1552 (2005).
Wattel S., Mircescu H.,
Venet, D., Burniat A., Franc, B., Andry, G., Van Sande J., Rocmans P.,
Detours V., Dumont J.E., Maenhaut C.
Gene expression in thyroid
autonomous adenoma provides insight on their pathology.
Oncogene 24: 6902-6916 (2005).
Fortemaison N, Blancquaert
S, Dumont JE, Maenhaut C, Aktories K, Roger PP, Dremier S.
Differential involvement of
the actin cytoskeleton in differentiation and mitogenesis of thyroid cells:
inactivation of Rho proteins contributes to cyclic adenosine
monophosphate-dependent
gene expression but prevents mitogenesis.
Endocrinology. 146(12):5485-95 (2005)
van Staveren W., Weiss D.,
Delys, L., Venet D., Cappello M., Andry G., Dumont J.E., Libert F., Detours
V., Maenhaut C.
Gene expression in human
thyrocytes and autonomous adenomas reveals suppression of negative feedbacks
in tumorigenesis.
Proc. Natl. Acad. Sci, 103, 413-418 (2006).
van Staveren W., Detours V.,
Dumont J.E., Maenhaut C.
Negative feedbacks in normal
cell growth and their suppression in tumorigenesis.
Cell Cycle 5, 571-572 (2006).
Paternot S, Arsenijevic T, Coulonval K, Bockstaele
L, Dumont JE, Roger PP.
Distinct specificities of
pRb phosphorylation by CDK4 activated by cyclin D1 or cyclin D3:
differential involvement in the distinct mitogenic modes of thyroid
epithelial cells.
Cell Cycle. 5(1):61-70
(2006).
|
Thyroid endocrinology
[ B .Corvilain , S.Costagliola , J.E.Dumont , F. Miot , P.Roger , J.Van Sande , G.Vassart ]
Current research programs include
the study of : the mechanisms of H2O2 production in thyrocytes, the regulation
cAMP and inositolphosphate regulatory cascades by the TSH receptor, structure-function
relationships of the TSH receptor, mechanisms of activation of the TSH receptor
by the autoantibodies of Graves’disease, control of the proliferation of
thyrocytes by cAMP- and growth factor-dependent mechanisms, the regulation of
gene expression in thyrocytes by cAMP, the mechanisms responsible for the
development of congenital hypothyroidism.
Main recent publications
De Deken X, Wang D, Many MC,
Costagliola S, Libert F, Vassart G, Dumont JE, Miot F.
Cloning of two human thyroid
cDNAs encoding new members of the NADPH oxidase family.
J Biol Chem. 275:23227-33 (2000).
Perry R, Heinrichs C,
Bourdoux P, Khoury K, Szots F, Dussault JH, Vassart G, Van Vliet G.
Discordance of monozygotic
twins for thyroid dysgenesis: implications for screening and for molecular
pathophysiology.
J Clin Endocrinol Metab. 87:4072-7 (2002).
Costagliola S, Bonomi M,
Morgenthaler NG, Van Durme J, Panneels V, Refetoff S, Vassart G.
Delineation of the
discontinuous-conformational epitope of a monoclonal antibody displaying full
in vitro and in vivo thyrotropin activity.
Mol Endocrinol. 18:3020-34. (2004).
Grasberger H, Vaxillaire M,
Pannain S, Beck JC, Mimouni-Bloch A, Vatin V, Vassart G, Froguel P, Refetoff
S.
Identification of a locus
for nongoitrous congenital hypothyroidism on chromosome 15q25.3-26.1.
Hum Genet. 118:348-55 (2005).
Grasberger H, Mimouni-Bloch
A, Vantyghem MC, van Vliet G, Abramowicz M, Metzger DL, Abdullatif H,
Rydlewski C, Macchia PE, Scherberg NH, van Sande J, Mimouni M, Weiss RE,
Vassart G, Refetoff S.
Autosomal dominant
resistance to thyrotropin as a distinct entity in five multigenerational
kindreds: clinical characterization and exclusion of candidate loci.
J Clin Endocrinol Metab. 90:4025-34 (2005).
Grasberger H, Ringkananont
U, Lefrancois P, Abramowicz M, Vassart G, Refetoff S.
Thyroid transcription factor
1 rescues PAX8/p300 synergism impaired by a natural PAX8 paired domain
mutation with dominant negative activity.
Mol Endocrinol. 19:1779-91 (2005)
|
Molecular genetics of hereditary diseases
[ M.Abramowicz , P.Cochaux, L.Duprez, J.Parma, G.Vassart]
Interactions
with the Medical Genetics department allow the ascertainment of families with
rare hereditary diseases. Studies aim at localizing the gene in the genome by
means of linkage analysis, or physical mapping of chromosomal deletions or
translocation breakpoints when available. The genomic interval is then inspected
for candidate genes, which in turn are studied for mutations in affected family
members. Examples of such rares diseases are primary microcephaly and
congenital corneal dystrophy. The linkage analysis and candidate gene approach
is also applied to complex inherited disorders like congenital athyreosis and
primary pulmonary hypertension.
Main recent publications
Vilain C, Rydlewski C,
Duprez L, Heinrichs C, Abramowicz M, Malvaux P, Renneboog B, Parma J,
Costagliola S, Vassart G.
Autosomal dominant transmission
of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8.
J.Clin.Endocrinol.Metab 86:234-8 ( 2001).
Perry R, Heinrichs C,
Bourdoux P, Khoury K, Szots F, Dussault JH, Vassart G, Van Vliet G.
Discordance of monozygotic
twins for thyroid dysgenesis: implications for screening and for molecular
pathophysiology.
J.Clin.Endocrinol.Metab 87:4072-7 (2002).
Smits G, Olatunbosun O,
Delbaere A, Pierson R, Vassart G, Costagliola S.
Ovarian hyperstimulation
syndrome due to a mutation in the follicle-stimulating hormone receptor. New
England Journal of Medicine 349:760-6 (2003).
Vilain C, Libert F, Venet D,
Costagliola S, Vassart G.
Small amplified RNA-SAGE: an
alternative approach to study transcriptome from limiting amount of mRNA.
Nucleic Acids Research 31:24 (2003).
Meeus L, Gilbert B,
Rydlewski C, Parma J, Roussie AL, Abramowicz M, Vilain C, Christophe D,
Costagliola S, Vassart G.
Characterization of a novel
loss of function mutation of PAX8 in a familial case of congenital hypothyroidism
with in-place, normal-sized thyroid
J Clin.Endocrinol.Metab 89:4285-91 (2004).
Pichon B, Vankerckhove S,
Bourrouillou G, Duprez L, Abramowicz MJ.
A translocation breakpoint
disrupts the ASPM gene in a patient with primary microcephaly.
Eur J Hum Genet 12(5):419-21 (2004).
Emiliani S, Gonzalez-Merino
E, Englert Y, Abramowicz M.
Comparison of the validity
of preimplantation genetic diagnosis for embryo chromosomal anomalies by
fluorescence in situ hybridization on one or two blastomeres.
Genet Test 8(1):69-72 (2004).
Abramowicz MJ, Ribai P,
Cordonnier M.
Congenital stationary night
blindness : report of an autosomal recessive family and linkage analysis.
Am J Med GenetA 132:76-9 (2005).
Thomée C, Schubert SW, Parma
J, Lê PQ, Hashemolhosseini S, Wegner M, Abramowicz MJ.
GCMB mutation in familial
isolated hypoparathyroidism with residual secretion of parathyroid hormone.
J Clin Endocrinol Metab 90:2487-92 (2005).
Tunca Y, Vurucu S, Parma J,
Akin R, Désir J, Baser I, Ergun A, Abramowicz M.
Prenatal diagnosis of
primary microcephaly in two consanguineous families by confrontation of
morphometry with DNA data.
Prenatal Diag, 26:449-453 (2006).
|
Molecular and Cellular Mechanisms of Brain development
[ P.Vanderhaeghen ] 
The cerebral
cortex is one of the most complex and important structures in our brain. The
mechanisms of formation of the cortex have direct relevance to several
diseases, such as epilepsy and mental disorders, as well as for the development
of rationally designed cell therapies for neurological conditions.
Our major goal is to understand better the genetic mechanisms controlling the
development of the cerebral cortex, from stem cells to neuronal networks.
Our main experimental model is the mouse, where we combine molecular and
cellular approaches to study cortical development, both in vivo (using
tools such as mouse transgenesis and in utero electroporation) and in vitro (using tools such as organotypic assays).
In other projects centered on human cortex development we try to identify genes
that underly the development and evolution of human-specific features in our
brain.
Finally, using mouse and human embryonic stem (ES) cells, we are developing
methods to produce specific types of cortical neurons, and to generate in vitro
models of human neuronal diseases.
Main recent publications
Dufour A, Seibt J, Passante
L, Depaepe V, Ciossek T, Frisen J, Kullander K, Flanagan J, Polleux F, and
Vanderhaeghen P .
Area-Specificity and
Topography of Thalamocortical Projections Controlled by Ephrin/Eph genes.
Neuron 39: 453-465 (2003) .
Seibt J, Schuurmans C,
Gradwhol G, Dehay C, Vanderhaeghen P , Guillemot F, and Polleux F.
Neurogenin2 specifies
the connectivity of thalamic neurons by controlling axon responsiveness to
intermediate target cues.
Neuron 39: 439-452 (2003).
Depaepe V, Suarez N,
Passante L, Dufour A, Gorski J, Jones K, Ledent C, and Vanderhaeghen P.
Ephrin signalling controls
brain size by regulating apoptosis of neural progenitors.
Nature 435: 1244-1250 (2005)
Lambot MA, Depasse F, Noel
JC, and Vanderhaeghen P.
Mapping labels in the
developing human visual system and the evolution of binocular vision.
J. Neurosci. 25: 7232-7237 (2005).
Egea J, Vig Nissen U, Dufour
A, Sahin M, Greer P, Kullander K, Mrsic-Flogel T, Greenberg ME, Kiehn O,
Vanderhaeghen P, Klein R.
Regulation of EphA4 Kinase
Activity Is Required for a Subset of Axon Guidance Decisions Suggesting a Key
Role for Receptor Clustering in Eph Function.
Neuron 47: 515-528 (2005).
Dufour A, Egea J, Kullander
K, Klein R, and Vanderhaeghen P.
Genetic Analysis of
EphA-Dependent Signalling Mechanisms Controlling Topographic Mapping in Vivo.
Development 133(22):4415-20 (2006).
Pollard K, Salama S, Lambert
N, Lambot M-A, Coppens S, Pedersen J, Katzman S, King B, Onodera C, Siepel A,
Kern A, Vanderhaeghen P, and Haussler D.
The Fastest Evolving Region
in the Human Genome is an RNA Gene Expressed During Early Neocortical
Development.
Nature 443: 167-172 (2006).
|
Gene
expression
[ D.Christophe , C.
Hobertus, C.Maenhaut ]
Studies aim
to the characterization of molecular mechanisms involved in the control of gene
expression mainly, but not only, in the thyroid. The identification of
transcripts and regulatory proteins is carried out, as well as the detailed
study of their function at the molecular level. Emphasis is put on the
investigation of the role of cAMP and tissue-specific factors in the
transcriptional control of genes involved in thyroid cell proliferation and
differentiation. Extension of this work to the identification of differentially
expressed genes between normal and tumor thyroid cells might help to identify
new molecular markers for diagnosis as well as new pharmacological targets.
Main recent publications
Deleu S., Savonet V., Behrends J., Dumont J.E.,
Maenhaut C.
Study of gene expression in
thyrotropin-stimulated thyroid cells by cDNA expression array : ID3
transcription modulating factor as an early response protein and tumor marker
in thyroid carcinomas.
Exp. Cell Res. 279, 62-70 (2002).
Detours V., Wattel S., Venet
D., Hutsebaut N., Bogdanova T., Tronko M., Dumont J.E., Franc B., Thomas G.,
Maenhaut C.
Absence of a specific
radiation signature in post-Chernobyl thyroid cancers.
Br. J. Cancer 92:1545-1552 (2005).
Wattel S., Mircescu H.,
Venet, D., Burniat A., Franc, B., Andry, G., Van Sande J., Rocmans P.,
Detours V., Dumont J.E., Maenhaut C.
Gene expression in thyroid
autonomous adenoma provides insight on their pathology.
Oncogene 24: 6902-6916 (2005).
van Staveren W., Weiss D.,
Delys, L., Venet D., Cappello M., Andry G., Dumont J.E., Libert F., Detours
V., Maenhaut C.
Gene expression in human
thyrocytes and autonomous adenomas reveals suppression of negative feedbacks
in tumorigenesis.
Proc. Natl. Acad. Sci, 103: 413-418 (2006).
van Staveren W., Detours V.,
Dumont J.E., Maenhaut C.
Negative feedbacks in normal
cell growth and their suppression in tumorigenesis.
Cell Cycle 5: 571-572 (2006).
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Simulation
of biological systems, bioinformatics, biostatistics.
[ V.De Maertelaer , V.
Detours, S.Swillens ]
The
quantitative interpretation of biological data requires the use of computer
assisted approaches.
A first approach consists of the statistical analysis of data in order to
support relevance and significance of biological observations.
A second approach deals with the elaboration and the computer simulation of
models in order to test the validity of intuitively proposed schemas of
regulation pathways. Theoretical studies have been especially conducted in the
field of second messenger-controlled cascades (cyclic AMP, InsP3 ,
Ca2+) and receptor activation (TSH receptor, InsP3-receptor-Ca2+-channel).
In a third approach, we apply the tools of bioinformatics to gene expression
data arising in cancer research, and in particular thyroid cancers. We are
currently focusing on two topics: the relation between ionizing radiations and
cancer initiation, and the diagnosis of thyroid malignancy. The first topic
rest on the comparison of expression profiles of thyroid cancers collected from
Ukrainian patients irradiated after the Chernobyl accident and from patients
with no history of exposure to radiation. This work aims at finding a radiation
fingerprint, and perhaps a radiation susceptibility signature distinguishing
these cancers. Thyroid tumors affects as much as 40% of the population after
40, yet while 5% of these are cancers, diagnostic is inconclusive in 20% of the
cases, resulting in many unnecessary thyroidectomies. Genome-wide expression
profiling could help solve this problem and help understand better the
morphology of thyroid tumors.
Main recent publications
d'Alcantara,P., S.N.Schiffmann, and S.Swillens.
Bidirectional synaptic
plasticity as a consequence of interdependent Ca2+-controlled phosphorylation
and dephosphorylation pathways.
European Journal of Neuroscience. 17:2521-2528 (2003).
Dupont,G., O.Koukoui,
C.Clair, C.Erneux, S.Swillens, and L.Combettes.
Ca2+ oscillations in
hepatocytes do not require the modulation of InSP3 3-kinase activity by Ca2+
Febs Letters. 534:101-105 (2003).
Van Sande,J., M.J.Costa,
C.Massart, S.Swillens, S.Costagliola, J.Orgiazzi, and J.E.Dumont.
Kinetics of
thyrotropin-stimulating hormone (TSH) and thyroid-stimulating antibody
binding and action on the TSH receptor in intact TSH receptor-expressing CHO
cells." Journal of Clinical
Endocrinology and Metabolism. 88:5366-5374 (2003).
Van Sande,J., M.J.Costa,
C.Massart, S.Swillens, S.Costagliola, J.Orgiazzi, and J.E.Dumont.
Kinetics of
thyrotropin-stimulating hormone (TSH) and thyroid-stimulating antibody binding
and action on the TSH receptor in intact TSH receptor-expressing CHO cells.
Journal of Clinical Endocrinology and Metabolism. 88:5366-5374 (2003).
Swillens,S., Goffard,J.C.,
Marechal,Y., De Kerchove,d.A., El Housni,H.
Instant evaluation of the
absolute initial number of cDNA copies from a single real-time PCR curve.
Nucleic Acids Res. 32 : e5,( 2004).
Urizar,E., Montanelli,L.,
Loy,T., Bonomi,M., Swillens,S., Gales,C., Bouvier,M., Smits,G., Vassart,G.,
Costagliola,S.
Glycoprotein hormone
receptors: link between receptor homodimerization and negative cooperativity.
EMBO J. 24 : 1954-1964 ( 2005).
Dessars,B., Heimann,P.,
Swillens,S., El Housni,H.
Limitations and practical
procedure in BclII-Ig heavy chain gene rearrangement real-time quantitative
polymerase chain reaction.
J. Mol. Diagn. 8 :133-136,( 2006).
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Tack,D., J.Widelec, V.De
Maertelaer, J.M.Bailly, C.Delcour, and P.A.Gevenois.
Comparison between low-dose
and standard-dose multidetector CT in patients with suspected chronic
sinusitis.
American Journal of Roentgenology. 181:939-944 (2003).
Tack,D., V.De Maertelaer,
and P.A.Gevenois.
Dose reduction in
multidetector CT using attenuation-based online tube current modulation.
AJR Am J Roentgenol. 181:331-334 (2003).
Tack,D., S.Sourtzis,
I.Delpierre, V.De Maertelaer, and P.A.Gevenois.
Low-dose unenhanced
multidetector CT of patients with suspected renal colic.
AJR Am J Roentgenol. 180:305-311 (2003).
Daelemans C, Smits G, de Maertelaer
V, Costagliola S, Englert Y, Vassart G, Delbaere A.
Prediction of severity of
symptoms in iatrogenic ovarian hyperstimulation syndrome
by follicle-stimulating hormone receptor Ser680Asn polymorphism.
J Clin Endocrinol Metab. 89(12):6310-5
(2004).
Bankier AA, O'Donnell CR, Mai
VM, Storey P, De Maertelaer V, Edelman RR, Chen Q.
Impact of lung volume on MR
signal intensity changes of the lung parenchyma.
J Magn Reson Imaging. 20(6):961-6
(2004).
Arvanitakis M, Van Laethem JL,
Parma J, De Maertelaer V, Delhaye M, Deviere J.
Predictive factors for
pancreatic cancer in patients with chronic pancreatitis in association
with K-ras gene mutation.
Endoscopy.36(6):535-42 (2004).
Keyzer C, Tack D, de
Maertelaer V, Bohy P, Gevenois PA, Van Gansbeke D.
Acute appendicitis:
comparison of low-dose and standard-dose unenhanced multi-detector row CT.
Radiology. 232(1):164-72 (2004).
Tack D, Bohy P, Perlot I, De
Maertelaer V, Alkeilani O, Sourtzis S, Gevenois PA.
Suspected acute colon
diverticulitis: imaging with low-dose unenhanced multi-detector row CT.
Radiology. 237(1):189-96 (2005).
Tack D, De Maertelaer V,
Petit W, Scillia P, Muller P, Suess C, Gevenois PA.
Multi-detector row CT
pulmonary angiography: comparison of standard-dose and simulated
low-dose techniques.
Radiology. 236(1):318-25 (2005).
Hainaux B, Agneessens E,
Bertinotti R, De Maertelaer V, Rubesova E, Capelluto E,
Moschopoulos C.
Accuracy of MDCT in
predicting site of gastrointestinal tract perforation.
AJR Am J Roentgenol. 187(5):1179-83 (2006).
Madani A, Zanen J, de
Maertelaer V, Gevenois PA.
Pulmonary emphysema:
objective quantification at multi-detector row CT
comparison with macroscopic and microscopic morphometry.
Radiology. 238(3):1036-43 (2006).
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Detours, V., Dumont, J. E., Bersini, H., &
Maenhaut, C.
Integration and Cross-Validation of High-Throughput
Gene Expression Data: Comparing Heterogenous Data Sets ,
FEBS Lett. 546 : 98-102, (2003).
Wattel, S., Mircescu, H., Venet, D., Burniat, A.,
Franc, B., Frank, S., Andry, G., Van Sande, J., Rocmans, P., Dumont, J. E.,
Detours, V. & Maenhaut, C
Gene Expression in Thyroid Autonomous Adenomas
Provides Insight on their Physiopathology
Oncogene 24 : 6902-16, (2005).
Detours, V., Wattel, S., Venet, D., Hutsebaut, N.,
Bogdanova, T., Tronko, M. D., Dumont, J. E., Franc, B., Thomas, G. &
Maenhaut, C.
Absence of a Specific Radiation Signature in
Post-Chernobyl Thyroid Cancers ,
British J. Cancer
92 : 1545-1552, (2005).
Van Staveren, C. G., Detours, V., Dumont, J. E.,
& Maenhaut, C,
Negative feedbacks in normal cell growth and their
suppression in tumorigenesis .
Cell Cycle 5 : 571-572, (2006).
Van Staveren, C. G., Weiss, D., Delys, L., Venet,
D., Cappello, M., Andry, G., Dumont, J. E., Libert, F., Detours, V., &
Maenhaut, C.
Gene Expression in TSH-treated Human Thyrocytes and
Autonomous Adenomas: Suppression of Negative Feedbacks in Tumorigenesis
Proc. Nat. Acad. Sci. USA 103 : 413–418,
(2006).
Detours, V., Dumont, J. E., & Maenhaut, C.
Systems Biology, Cell Specificity and Physiology
Theories in Medicine, Paton R. & McNamara L. Eds. Elsevie, (2006).
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Technology “plateforms”
The following technologies are available in the frame of groups in which
they have been developed for their own research programs
Proteomic plateform
[ David Communi ]
Our major
goals are the discovery of novel molecules involved in signal transduction (immune
and inflammatory responses), i.e. ligands for orphan GPCR and intracellular
second messengers, as well as the study of their post-translational
modifications (e.g. proteolytic processing, phosphorylation,...). Current
applications concern essentially the purification of peptides and proteins by
2D-electrophoresis and multidimensional HPLC, followed by their
characterization by mass spectrometry (MALDI and nanoLC Q-TOF systems) before
physiological study.
Main recent publications
Communi D., Gevaert K.,
Demol H., Vandekerckhove J. and Erneux
A novel receptor-mediated
regulation mechanism of type I inositol polyphosphate 5-phosphatase by
calcium:calmodulin-dependent protein kinase II phosphorylation.
J. Biol. Chem. 276: 38738-38747 (2001).
Wittamer V., Franssen J.-D.,
Vulcano M., Mirjolet J.-F., Le Poul E., Migeotte I., Brézillon S., Tyldesley
R., Blanpain C., Detheux M., Mantovani A., Sozzani S., Vassart G., Parmentier
M. and Communi D.
Specific recruitment of
antigen-presenting cells by chemerin, a novel processed ligand from human
inflammatory fluids.
J. Exp. Med. 198: 977-985 (2003).
Migeotte I., Riboldi E.,
Franssen J.-D., Grégoire F., Loison C., Wittamer V., Detheux M., Robberecht
P., Costagliola S., Vassart G., Sozzani S., Parmentier M. and Communi D.
Identification and
characterization of an endogenous chemotactic ligand specific for FPRL2.
J. Exp. Med. 201: 83-93 (2005).
Wittamer V., Bondue B.,
Guillabert A., Vassart G., Parmentier M. and Communi D.
Neutrophil-mediated
maturation of chemerin : a link between innate and adaptive immunity.
J. Immunol. 175: 487-493 (2005).
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Two hybrid
[ I.Pirson ]
Contribution to
the elucidation of a protein's function can benefit greatly from the
identification of its protein partners. The two-hybrid in vivo method of
screening for protein/protein interactions in yeast, in now enabling research
teams to identify potential protein interactors of a variety of proteins of
interest. Our lab's main research thrust is focused on protein/protein
interactions in the field of signal transduction. We have developed diverse
biochemical and cellular biology methods to support the results yielded by the
two-hybrid system and to address the physiological relevance of the identified
complexes.
Main recent publications
Mircescu*H., Steuve*S.,
Savonet V., Degraef C., Mellor H., Dumont J.E., Maenhaut C., Pirson I.
Identification and
characterization of a novel activated RhoB binding protein containing a PDZ
domain and whose expression is specifically modulated in thyroid cells by
cAMP.
European Journal of Biochemistry 269: 6241-6249 (2002).
Vandenbroere I., Paternotte
N., Dumont J.E., Erneux C., Pirson I.
The c-Cbl associated protein
(CAP) and c-Cbl are two new partners of the SH2-containing inositol
polyphosphate 5- phosphatase SHIP2.
Biochemical and Biophyical Communications 300 : 494-500 (2003).
Arsenijevic T., Degraef C.,
Dumont J.E., Roger P.P.and Pirson I.
A novel partner for cyclins
D: Protein Kinase A-anchoring protein AKAP95.
Biochemical Journal 378: 673-679 (2003).
Jacobs C., Onnockx S,
Vandenbroere I. and Pirson I.
Endogenous SHIP2 does not
localize in lipid rafts in 3T3-L1 adipocytes.
FEBS Letters 565: 70-74 (2004).
Paternotte N., Zhang J.,
Vandenbroere I., Backers K., Blero D., Kioka N., Vanderwinden J-M, Pirson I.,
and Erneux C.
SHIP2 interaction with the
cytoskeletal protein Vinexin.
FEBS Journal 272: 6052-6066
(2005)
Arsenijevic T, Degraef C, Dumont JE, Roger PP,
Pirson I.
G1/S Cyclins interact with
regulatory subunit of PKA via A-kinase anchoring protein, AKAP95.
Cell Cycle. 11 :1217-22 (2006).
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Transgenesis
[ C.Ledent , B.Robaye, S.Schurmans , P.Vanderhaeghen]
The IRIBHM has developed a
mouse transgenic facility in the latest eighties. Addition transgenesis, by
microinjection of DNA constructs into fertilized mouse eggs, and gene
replacement, resulting from the genetic manipulation of embryonic stem cells
(ES), are available in the institute. These techniques have been used to
generate models of thyroid diseases and to study the role in vivo of G protein
coupled receptors, signalling proteins and factors involved in brain
development.
Main recent publications
Depaepe V, Suarez N,
Passante L, Dufour A, Gorski J, Jones K, Ledent C, and Vanderhaeghen P.
Ephrin signalling controls
brain size by regulating apoptosis of neural progenitors.
Nature 435: , 1244-1250 (2005)
Ledent C, Demeestere I, Blum
D, Petermans J, Hamalainen T, Smits G, Vassart G.
Premature ovarian aging in
mice deficient for Gpr3.
Proc.Natl.Acad.Sci.U.S A 102:8922-6 (2005).
Laurent P, Becker JA,
Valverde O, Ledent C, de Kerchove d'Exaerde A, Schiffmann SN,
Maldonado R, Vassart G, Parmentier M.
The prolactin-releasing
peptide antagonizes the opioid system through its receptor GPR10.
Nat Neurosci. 8(12):1735-4 (2005).
Jardinaud F, Crete D, Canestrelli C, Ledent C,
Roques BP, Noble F.
CB1 receptor knockout mice
show similar behavioral modifications to wild-type mice when
enkephalin catabolism is inhibited.
Brain Res. 1063(1):77-83 (2005).
Ledent C, Demeestere I, Blum
D, Petermans J, Hamalainen T, Smits G, Vassart G.
Premature ovarian aging in
mice deficient for Gpr3.
Proc Natl Acad Sci U S A. 102(25):8922-6 (2005).
Laurent P, Becker JA, Valverde
O, Ledent C, de Kerchove d'Exaerde A, Schiffmann SN,
Maldonado R, Vassart G, Parmentier M.
The prolactin-releasing
peptide antagonizes the opioid system through its receptor GPR10.
Nat Neurosci. 8(12):1735-41 (2005).
Ghanem E, Lovdahl C, Dare E,
Ledent C, Fredholm BB, Boeynaems JM, Van Driessche W,
Beauwens R.
Luminal adenosine stimulates
chloride secretion through A1 receptor in mouse jejunum.
Am J Physiol Gastrointest Liver Physiol. 288(5):G972-7 (2005).
Mievis S, Levivier M,
Vassart G, Brotchi J, Ledent C, Blum D.
Citicoline is not protective
in experimental models of Huntington's disease.
Neurobiol Aging. 2006
Castane A, Soria G, Ledent
C, Maldonado R, Valverde O.
Attenuation of
nicotine-induced rewarding effects in A2A knockout mice.
Neuropharmacology.51(3):631-40 (2006).
Mikics E, Dombi T, Barsvari
B, Varga B, Ledent C, Freund TF, Haller J.
The effects of cannabinoids
on contextual conditioned fear in CB1 knockout and CD1 mice.
Behav Pharmacol. 17(3):223-30 2006.
Short JL, Ledent C, Borrelli
E, Drago J, Lawrence AJ.
Genetic interdependence of
adenosine and dopamine receptors: evidence from receptor
knockout mice.
Neuroscience. 139(2):661-70 (2006).
Castane A, Celerier E,
Martin M, Ledent C, Parmentier M, Maldonado R, Valverde O.
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