Nicalin and its binding partner Nomo are novel Nodal signaling antagonists.
Nodals are signaling factors of the transforming growth factor-beta (TGFbeta) superfamily with a key role in vertebrate development. They control a variety of cell fate decisions required for the establishment of the embryonic body plan. We have identified two highly conserved transmembrane proteins, Nicalin and Nomo (Nodal modulator, previously known as pM5), as novel antagonists of Nodal signaling. Nicalin is distantly related to Nicastrin, a component of the Alzheimer's disease-associated gamma-secretase, and forms a complex with Nomo. Ectopic expression of both proteins in zebrafish embryos causes cyclopia, a phenotype that can arise from a defect in mesendoderm patterning mediated by the Nodal signaling pathway. Accordingly, downregulation of Nomo resulted in an increase in anterior axial mesendoderm and the development of an enlarged hatching gland. Inhibition of Nodal signaling by ectopic expression of Lefty was rescued by reducing Nomo levels. Furthermore, Nodal- as well as Activin-induced signaling was inhibited by Nicalin and Nomo in a cell-based reporter assay. Our data demonstrate that the Nicalin/Nomo complex antagonizes Nodal signaling during mesendodermal patterning in zebrafish.
Haffner
Christof
C
Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Munich, Germany. chaffner@med.uni-muenchen.de
Frauli
Mélanie
M
Topp
Stephanie
S
Irmler
Martin
M
Hofmann
Kay
K
Regula
Jörg T
JT
Bally-Cuif
Laure
L
Haass
Christian
C
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D019521:Body Patterning; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008970:Molecular Weight; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D055457:Nodal Protein; D010802:Phylogeny; D016548:Prosencephalon / Q000196:embryology / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D019170:Somites / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C526007:NODAL protein, human; C501109:NOMO3 protein, human; D055457:Nodal Protein; D016212:Transforming Growth Factor beta; D029961:Zebrafish Proteins; C501106:ncln protein, zebrafish; C413604:nicastrin protein; C501108:nomo protein, zebrafish; D053829:Amyloid Precursor Protein Secretases