Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis

Abstract

Bone morphogenetic proteins (Bmps) are members of the transforming growth factor ␤ (TGF␤) superfamily that play critical roles during mouse embryogenesis. Signaling by Bmp receptors is mediated mainly by Smad proteins. In this study, we show that a targeted null mutation of Ecsit, encoding a signaling intermediate of the Toll pathway, leads to reduced cell proliferation, altered epiblast patterning, impairment of mesoderm formation, and embryonic lethality at embryonic day 7.5 (E7.5), phenotypes that mimic the Bmp receptor type1a ( The transforming growth factor ␤ (TGF␤) superfamily comprises a large number of secreted polypeptide factors, with >30 members in mammals and about a dozen in worms and flies. TGF␤s control numerous cellular functions and regulate many developmental and homeostatic processes. However, a simple scheme lies at the core of all TGF␤ signaling pathways. The receptor for TGF␤ is a complex of two distinct transmembrane proteins, known as type I and type II receptors, with serine/threonine kinase activity within their cytoplasmic domains. Ligand binding to the type II receptor induces the association, phosphorylation, and activation of the type I receptor. The activated type I receptor then signals through the Smad family of signal transducers. Smad proteins can be divided into three classes: receptor-regulated Smads or R-Smads (Smad1, 2, 3, 5, 8); co-Smad (Smad4); and inhibitory Smads or I-Smads (Smad6 and 7). After stimulation, R-Smads are phosphorylated by type I receptors, detach from the receptor complex, associate with Smad4, and accumulate in the nucleus, where they regulate gene expression by interacting with various cofactors. Smad access to target genes and the recruitment of transcriptional coactivators or corepressors to these genes depend on cell-type-specific cofactors. Although many Smad cofactors have been identified for the TGF␤ pathways, very few are known for the Bmp pathways (Wrana 2000;Shi and Massague 2003).Genetic evidence has shown that Bmp4 plays pivotal roles in the gastrulation of mouse embryo, a process that lays down the future body plan (Lu et al. 2001). Bmp4 regulates the proliferation, survival, and patterning of the epiblast; the induction of primordial germ cell precursors; and formation of the mesoderm (Mishina et al. 1995;Winnier et al. 1995;Lawson et al. 1999). Bmp4 signals through Bmpr1a, a type I Bmp receptor, to induce the up-regulation of target genes including Tlx2, a homeobox gene that is a critical effector of Bmp signaling

NF-κB and the immune response

“…ECSIT binds to TRAF6 and is required for TLR and interleulin-1 (IL-1) signaling, but not TNFsignaling (Kopp et al, 1999;Xiao et al, 2003). Although these studies suggested that ECSIT functions by recruiting and activating the kinase MEKK1 (mitogen activated protein kinase or ERK kinase (MEK) kinase 1) (Kopp et al, 1999;Xiao et al, 2003), the role of MEKK1 in TLR signaling remains unclear (Xia et al, 2000;Yujiri et al, 2000). MEKK3-deficient cells, however, do not transcribe IL-6 following TLR4 or IL-1R stimulation and exhibit delayed and weakened NF-kB DNA binding following lipopolysaccharide (LPS) stimulation (Huang et al, 2004).…”

Interleukin-1 (IL-1)-induced TAK1-dependent Versus MEKK3-dependent NFκB Activation Pathways Bifurcate at IL-1 Receptor-associated Kinase Modification

“…Once activated, TAK1 leads to the phosphorylation of IKK␤ and MKK6, resulting in the activation of both the JNK and NFB signaling pathways. In addition to TAK1, MEKK2 and MEKK3 have also been implicated in the activation of IKK and MAPK, leading to the activation of NFB and JNK (25)(26)(27)(28). The detailed signaling mechanism is not clear.…”

Ubiquitin-mediated activation of TAK1 and IKK

“…However, genetic studies have shown that MEKK1 is dispensable for NF-kB activation (Yujiri et al, 2000). Mouse knockout experiments showed that ECSIT is required for BMP signalling but so far there is no genetic evidence that it is required for NF-kB or MAPK activation (Xiao et al, 2003).…”