Soluble Frizzled-Related Protein 1 Is Estrogen Inducible in Bone Marrow Stromal Cells and Suppresses the Earliest Events in Lymphopoiesis

Abstract

It has long been known that lymphopoiesis is transiently suppressed during pregnancy, which can be experimentally simulated by estrogen treatment. We now confirm with Rag1/GFP reporter mice that early lymphoid progenitors in the lineage marker− c-kithigh ScaI+, hematopoietic stem cell-enriched fraction of bone marrow are particularly depressed in these circumstances. Hematopoietic and environmental cells are both potential hormone targets and, because of this complexity, very little is known regarding mechanisms. We have now identified soluble Frizzled-related protein (sFRP)1 as an estrogen-inducible gene in stromal cells, whose expression corresponded to inability to support lymphopoiesis. Bone-lining stromal cells express sFRP1, and the transcripts were elevated by pregnancy or estrogen injection. Estrogen receptor-α was essential for both lymphoid suppression and induction of the sFRP family. SFRP1 has been mainly described as an antagonist for complex Wnt signals. However, we found that sFRP1, like Wnt3a, stabilized β-catenin and blocked early lymphoid progression. Myeloerythroid progenitors were less affected by sFRP1 in culture, which was similar to estrogen with respect to lineage specificity. Hematopoietic stem cells expressed various Frizzled receptors, which markedly declined as they differentiated to lymphoid lineage. Thus, hormonal control of early lymphopoiesis in adults might partly relate to sFRP1 levels.

Secreted-frizzled related protein 1 is a transcriptional repression target of the t(8;21) fusion protein in acute myeloid leukemia

“…43 Previous studies showed that SFRP1 can modulate canonical and noncanonical Wnt signaling both positively and negatively. [44][45][46][47] Here, we demonstrated that SFRP1 selectively inhibited the canonical pathway in t(8;21)-leukemia cells. This observation was also supported by significant down-regulation of canonical Wnt/␤-catenin target genes (CCND1 and MYC) but not noncanonical Wnt targets (PCDH8, JUN, ATF2, and SUZ12) 34,44,48 in Kasumi-1 cells after SFRP1 treatment.…”

Secreted frizzled-related proteins are required for Wnt/β-catenin signalling activation in the vertebrate optic cup

“…This alternative view offers a possible explanation for previous results showing that Sfrp1 is required for positive regulation of -catenin in, for example, hematopoietic progenitors (Renstrom et al, 2009;Yokota et al, 2008). RESEARCH REPORT Sfrp in Wnt signalling activation …”

Estrogen receptor signaling promotes dendritic cell differentiation by increasing expression of the transcription factor IRF4

“…One possibility was that DC precursors in ER␣ Ϫ/Ϫ mice are defective due to the absence of factors supplied by estrogen-responsive BM stromal cells in vivo. 29 To determine whether the effect of ER␣ signaling on IRF4 expression was intrinsic to hematopoietic DC precursors, we generated ER␣ ϩ /ER␣ Ϫ/Ϫ mixed BM chimeric mice, and BM cells from these chimeric mice were placed into GM-CSF-driven cultures. After 7 days, ER␣ ϩ cells expressed higher amounts of IRF4 and had developed into both CD11b hi and CD11b int DC subsets, whereas ER␣ Ϫ/Ϫ cells expressed lower amounts of IRF4 and had developed primarily into CD11b hi DCs ( Figure 5E,F).…”