Sfrp1, Sfrp2, and Sfrp5 regulate the Wnt/β‐catenin and the planar cell polarity pathways during early trunk formation in mouse

Satoh, Wataru; Matsuyama, Makoto; Takemura, Hiromasa; Aizawa, Shinichi; Shimono, Akihiko

doi:10.1002/dvg.20369

Cited by 114 publications

(93 citation statements)

References 66 publications

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“…Despite restricted mRNA expression, Sfrp proteins efficiently diffuse in the extracellular space 17 and Sfrp1 was immunodetected, albeit at low levels, also in the neural retina (Fig. S1), supporting the proposed Sfrp functional redundancy 9,11,12 .…”

Section: Sfrp1 and Sfrp2 Are Essential For Proper Eye Developmentsupporting

confidence: 62%

“…First, Sfrp function might be redundant, because genetic inactivation of individual family members in mice seems to have little effect on embryonic development 9,10 . Double inactivation of Sfrp1 and Sfrp2 causes instead a variety of alterations 9,11,12 , some of which are worsened by the additional inactivation of Sfrp5 9,11 . Second, Sfrps have Wnt-independent functions 9,12 because Sfrp null phenotypes are only partially explained by overactivation of Wnt/βcatenin signaling 11 or alterations in the non-canonical Wnt/PCP pathway.…”

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confidence: 99%

“…Double inactivation of Sfrp1 and Sfrp2 causes instead a variety of alterations 9,11,12 , some of which are worsened by the additional inactivation of Sfrp5 9,11 . Second, Sfrps have Wnt-independent functions 9,12 because Sfrp null phenotypes are only partially explained by overactivation of Wnt/βcatenin signaling 11 or alterations in the non-canonical Wnt/PCP pathway. Consistent with this notion, several studies have implicated individual Sfrps in the Wnt-independent regulation of other cell signaling mechanisms.…”

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confidence: 99%

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SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

et al. 2011

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It is well established that embryonic mouse retinal neurogenesis requiresNotch and Wnt signaling are also required for the development of vertebrate neural retina.This structure develops from a neuroepithelium composed of multipotent progenitors, which undergo a series of competence states to give rise to six neuronal and one glial cell types 2 . As progenitor cells produce the various cell types, Notch through lateral inhibition, maintains neighboring cells in a multipotent, proliferative state, ensuring that sufficient numbers of progenitors are retained for consecutive waves of neurogenesis. Thus, downregulation of Notch is a prerequisite for retinal neuronal differentiation 2 .Wnt/βcatenin signaling has also been implicated in the proliferation of vertebrate retinal precursors. However, in the mouse embryonic neural retina this function is limited to progenitor cells located in the periphery 3, 4 . In contrast, Wnt/βcatenin signaling is not active in the central retina and cell proliferation and differentiation proceed normally in mice with conditional deletion of βcatenin in the neural retina, although retinal lamination is altered 5 .Similarly, retinal specific inactivation of Fzd5, a non-canonical Wnt receptor mostly impacts on retinal vasculature formation but has no effect on neurogenesis 6 By analyzing the functional consequences of Sfrp1 and Sfrp2 compound inactivation during mouse retinal neurogenesis, we demonstrate here a novel and Wnt-independent role of Sfrps in the regulation of Notch signaling. We explain this finding by demonstrating that Sfrps can bind and downregulate the activity of ADAM10, a metalloprotease with multiple substrates including Notch, N-cadherin and APP. 4 RESULTS Sfrp1 and Sfrp2 are essential for proper eye developmentSfrp1 and Sfrp2 are expressed during murine eye development with a complementary pattern that includes all eye structures 7 . Sfrp1 transcripts are localized to the optic cup periphery and the retina pigmented epithelium from E10.5, while Sfrp2 is predominant in the neural retina (Fig. S1). Despite restricted mRNA expression, Sfrp proteins efficiently diffuse in the extracellular space 17 and Sfrp1 was immunodetected, albeit at low levels, also in the neural retina (Fig. S1), supporting the proposed Sfrp functional redundancy 9, 11, 12 .Accordingly, the eye of Sfrp1 and Sfrp2 single null embryos appeared histologically normal.In contrast at E16.5, the latest viable stage, the eyes of Sfrp1 -/-;Sfrp2 -/-compound mutants (n=20) were smaller than those of control littermates (n=30) with morphological visible alterations, including dorsal peripheral defects, reduction of the lens size, abnormal cornea and eye lid formation, increased thickness of the neural retina and abnormal vitreal accumulation of mesenchyme-derived angioblasts that normally form the hyaloid artery, the major vascular structure of the embryonic eye (Fig. S2). Inactivation of Sfrp1/2 alters retinal neurogenesisMultipotent progenitors in the neural retina generates neuronal and one glial cells wi...

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Section: Sfrp1 and Sfrp2 Are Essential For Proper Eye Developmentsupporting

confidence: 62%

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confidence: 99%

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confidence: 99%

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SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

et al. 2011

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“…Unlike Dkks, which specifically inhibit Wnt/b-catenin signaling, sFRPs can also inhibit noncanonical Wnt/PCP ( planar cell polarity) signaling (Li et al 2008b;Satoh et al 2008;Matsuyama et al 2009;Sugiyama et al 2010), which is not surprising, as they bind to both types of Wnts. Inhibition of PCP signaling, which antagonizes Wnt/b-catenin signaling (Yan et al 2001;Schwarz-Romond et al 2002;Simons et al 2005;Li et al 2011), may also explain why sFRPs can activate Wnt/b-catenin signaling (Swain et al 2005).…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…sFRPs show a dynamic, partly overlapping, but also distinct expression pattern. To examine their roles in embryogenesis, single Sfrp1, Sfrp2, and Sfrp5 knockout mice (Leaf et al 2006;Satoh et al 2006), as well as different combinations of double-and triple-mutant mouse lines carrying homozygous or heterozygous mutations of two or all three genes, have been generated (Table 1) (Satoh et al 2008). Apart from Sfrp1 2/2 / Sfrp2 2/2 double-mutant and Sfrp1 2/2 / Sfrp2 2/2 /Sfrp5 2/2 triple-mutant mice, the other mutant mice are viable and fertile and have no obvious abnormalities in gross morphology, indicative of the redundant role of Sfrps in embryonic development.…”

Section: Role Of Sfrps In Embryonic Development and Pathological Eventsmentioning

confidence: 99%