Sfrp1andSfrp2regulate anteroposterior axis elongation and somite segmentation during mouse embryogenesis

Abstract

Regulation of Wnt signaling is essential for embryonic patterning. Sfrps are secreted Wnt antagonists that directly interact with the Wnt ligand to inhibit signaling. Here, we show that Sfrp1 and Sfrp2 are required for anteroposterior (AP) axis elongation and somitogenesis in the thoracic region during mouse embryogenesis. Double homozygous mutations in Sfrp1 and Sfrp2 lead to severe shortening of the thoracic region. By contrast, a homozygous mutation in one or the other exerts no effect on embryogenesis, indicating that Sfrp1 and Sfrp2 are functionally redundant. The defect of a shortened thoracic region appears to be the consequence of AP axis reduction and incomplete somite segmentation. The reduction in the AP axis is partially due to abnormalities in cell migration of pre-somitic mesoderm from the end of gastrulation. Aberrant somite segmentation is associated with altered oscillations of Notch signaling, as evidenced by abnormal Lfng and Hes7 expression during somitogenesis in the thoracic region. This study suggests that Wnt regulation by Sfrp1 and Sfrp2 is required for embryonic patterning.

SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

“…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 .…”

“…Loss of Sfrp function instead bespoke for two additional important features. 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 .…”

“…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.…”

Comprehensive profiling reveals mechanisms of SOX2-mediated cell fate specification in human ESCs and NPCs

“…WLS and SFRP2, two important regulators of Wnt signaling, are novel direct targets of SOX2 and mediate SOX2's function in hESCs. In fact, both Wls and Sfrp2 are needed for the axis formation in mouse, although functional redundancy between SFRP family members exists [45,46]. In human, both WLS and SFRP2 have been implicated in various cancers.…”

Molecular regulation of kidney development: is the answer blowing in the Wnt?

“…How these results relate to the in vivo situation is unclear. Recent studies indicate that sFrp1 and 2 play redundant roles during embryogenesis [103]. Embryos lacking both genes die in utero with anterior-posterior patterning defects, a phenotype that is similar to that of Wnt5a null embryos.…”