Kremen proteins interact with Dickkopf1 to regulate anteroposterior CNS patterning.
A gradient of Wnt/beta-catenin signalling formed by posteriorising Wnts and anteriorising Wnt antagonists regulates anteroposterior (AP) patterning of the central nervous system (CNS) during Xenopus gastrulation. In this process, the secreted Wnt antagonist Dkk1 functions in the Spemann organiser and its anterior derivatives by blocking Wnt receptors of the lipoprotein receptor-related protein (LRP) 5 and 6 class. In addition to LRP6, Dkk1 interacts with another recently identified receptor class, the transmembrane proteins Kremen1 (Krm1) and Kremen2 (Krm2) to synergistically inhibit LRP6. We have investigated the role of Krm1 and Krm2 during early Xenopus embryogenesis. Consistent with a role in zygotic Wnt inhibition, overexpressed Krm anteriorises embryos and rescues embryos posteriorised by Wnt8. Antisense morpholino oligonucleotide (Mo) knockdown of Krm1 and Krm2 leads to deficiency of anterior neural development. In this process, Krm proteins functionally interact with Dkk1: (1) in axis duplication assays krm2 synergises with dkk1 in inhibiting Wnt/LRP6 signalling; (2) krm2 rescues microcephalic embryos induced by injection of inhibitory anti-Dkk1 antibodies; and (3) injection of krm1/2 antisense Mo enhances microcephaly induced by inhibitory anti-Dkk1 antibodies. The results indicate that Krm proteins function in a Wnt inhibition pathway regulating early AP patterning of the CNS.
Davidson
Gary
G
Division of Molecular Embryology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Mao
Bingyu
B
del Barco Barrantes
Ivan
I
Niehrs
Christof
C
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D019521:Body Patterning; D002490:Central Nervous System / Q000196:embryology*; D003001:Cloning, Molecular; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary / Q000378:metabolism; D051157:Frizzled Receptors; D005775:Gastrula / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010802:Phylogeny; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism* / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013997:Time Factors; D014018:Tissue Distribution; D051153:Wnt Proteins; D014981:Xenopus / Q000196:embryology; D029867:Xenopus Proteins / Q000378:metabolism; D029961:Zebrafish Proteins
D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D051157:Frizzled Receptors; D006657:Histones; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C501127:Dkk1 protein, mouse; C486077:Kremen1 protein, mouse; C110182:dkk1 protein, Xenopus; C501128:dkk1b protein, zebrafish; C471148:kremen1 protein, Xenopus; C471149:kremen2 protein, Xenopus; C495248:wnt8a protein, Xenopus; C094521:wnt8a protein, zebrafish