title: Notum is required for neural and head induction via Wnt deacylation, oxidation, and inactivation.
abstract: Secreted Wnt morphogens are essential for embryogenesis and homeostasis and require a lipid/palmitoleoylate modification for receptor binding and activity. Notum is a secreted Wnt antagonist that belongs to the α/β hydrolase superfamily, but its mechanism of action and roles in vertebrate embryogenesis are not fully understood. Here, we report that Notum hydrolyzes the Wnt palmitoleoylate adduct extracellularly, resulting in inactivated Wnt proteins that form oxidized oligomers incapable of receptor binding. Thus, Notum is a Wnt deacylase, and palmitoleoylation is obligatory for the Wnt structure that maintains its active monomeric conformation. Notum is expressed in naive ectoderm and neural plate in Xenopus and is required for neural and head induction. These findings suggest that Notum is a prerequisite for the "default" neural fate and that distinct mechanisms of Wnt inactivation by the Tiki protease in the Organizer and the Notum deacylase in presumptive neuroectoderm orchestrate vertebrate brain development.
authors.affiliation: Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xinjun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Seong-Moon
authors.initials: SM
authors.lastname: Cheong
authors.affiliation: Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nathalia G
authors.initials: NG
authors.lastname: Amado
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Alice H
authors.initials: AH
authors.lastname: Reis
authors.affiliation: Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bryan T
authors.initials: BT
authors.lastname: MacDonald
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Matthias
authors.initials: M
authors.lastname: Zebisch
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Jose Garcia
authors.initials: JG
authors.lastname: Abreu
authors.affiliation: Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: xi.he@childrens.harvard.edu.
authors.forename: Xi
authors.initials: X
authors.lastname: He
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics; D004475:Ectoderm / Q000378:metabolism; D004625:Embryo, Nonmammalian; D004950:Esterases / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D057809:HEK293 Cells; D006257:Head / Q000196:embryology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D060172:Morpholinos; D054258:Neural Plate / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D060172:Morpholinos; D051153:Wnt Proteins; D029867:Xenopus Proteins; D019308:Palmitic Acid; D004950:Esterases; C000596390:Notum protein, human