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Secreted frizzled-related protein 2 (sFRP2) redirects non-canonical Wnt signaling from Fz7 to Ror2 during vertebrate gastrulation

Brinkmann, Eva-Maria

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Abstract

Proper cell movements require balanced activities of different signaling cascades, but factors regulating this interplay on the molecular level are poorly characterized. During embryogenesis, convergent extension (CE) movements are mainly regulated by three branches of non-canonical Wnt signaling: Ror2 mediated signaling, Frizzled mediated classical Wnt/PCP signaling, and the Wnt/Ca2+ signaling pathway.Secreted frizzled-related proteins (sFRPs) are known as inhibitors or biphasic modulators of Wnt/ß-catenin signaling but less is known about their function in ß-catenin independent Wnt pathways. Here, I show that secreted frizzled-related protein 2 (sFRP2), a member of the sFRP family, is required for morphogenesis and papc expression during Xenopus gastrulation. Notably, sFRP2 redirects non-canonical Wnt signaling from Fz7 to Ror2. During this process, sFRP2 promotes Ror2 signal transduction by stabilizing Wnt5a/Ror2 complexes at the membrane while it inhibits Fz7 signaling, probably by blocking Fz7 receptor endocytosis. Direct interaction of the two receptors via their CRDs also promotes Ror2 mediated papc expression but inhibits Fz7 signaling. Furthermore, other Fz-CRD containing proteins, such as other sFRP1 and frzb2 can also mediate this function. While the cysteine-rich domain (CRD) of sFRP2 is sufficient for Ror2 activation, the NTR domain of sFRP2 seems to be important for efficient Fz7 inhibition since the CRD alone could not prevent Fz7 receptor internalization. Based on my results, I propose that sFRPs act as a molecular switch channeling the signal input for different non-canonical Wnt pathways during vertebrate gastrulation.

Translation of abstract (German)

Zellbewegungen erfordern streng regulierte und aufeinander abgestimmte Signale, welche jedoch derzeit noch weitgehend ungeklärt sind. Während der Embryogenese werden konvergente Extensionsbewegungen hauptsächlich durch drei nicht kanonische Wnt- Signalwege reguliert: 1. Durch Ror2 vermittelte Signaltransduktion, 2. Durch den klassische Wnt/PCP Signalweg und 3. Durch die Wnt/Ca2+ Signalkaskade. Studien haben bereits mehrfach gezeigt, dass secreted frizzled-related proteins (sFRPs) den kanonischen Wnt/β-catenin Signalweg modulieren können.

Item Type: Dissertation
Supervisor: Özbek, PD Dr. Suat
Date of thesis defense: 18 December 2015
Date Deposited: 01 Feb 2016 10:14
Date: 2016
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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