Extracellular Regulation of BMP Signaling in Vertebrates: A Cocktail of Modulators

Abstract

The transforming growth factor-beta (TGF-beta) superfamily contains a variety of growth factors which all share common sequence elements and structural motifs. These proteins are known to exert a wide spectrum of biological responses on a large variety of cell types in both vertebrates and invertebrates. Many of them have important functions during embryonic development in pattern formation and tissue specification, and in adult tissues, they are involved in processes such as wound healing, bone repair, and bone remodeling. The family is divided into two general branches: the BMP/GDF and the TGF-beta/Activin/Nodal branches, whose members have diverse, often complementary effects. It is obvious that an orchestered regulation of different actions of these proteins is necessary for proper functioning. The TGF-beta family members act by binding extracellularly to a complex of serine/threonine kinase receptors, which consequently activate Smad molecules by phosphorylation. These Smads translocate to the nucleus, where they modulate transcription of specific genes. Three levels by which this signaling pathway is regulated could be distinguished. First, a control mechanism exists in the intracellular space, where inhibitory Smads and Smurfs prevent further signaling and activation of target genes. Second, at the membrane site, the pseudoreceptor BAMBI/Nma is able to inhibit further signaling within the cells. Finally, a range of extracellular mediators are identified which modulate the functioning of members of the TGF-beta superfamily. Here, we review the insights in the extracellular regulation of members of the BMP subfamily of secreted growth factors with a major emphasis on vertebrate BMP modulation.

Shh/BMP‐4 signaling pathway is essential for intestinal epithelial development during Xenopus larval‐to‐adult remodeling

“…In the present study, we performed the functional analysis of BMP-4 in the X. laevis postembryonic intestine by adding BMP-4 and Chordin proteins to the culture medium in vitro. It is generally known that Chordin antagonizes BMP-2 and -7 in addition to BMP-4 (Balemans and Hul, 2002). However, BMP-2 and -7 have not yet been identified as TH response genes, and their mRNAs were not detected by RT-PCR throughout X. laevis intestinal remodeling (our unpublished data).…”

“…Next, we investigated effects of BMP-4 protein and its antagonist, Chordin, on the X. laevis intestinal remodeling by using the organ culture system established previously (Ishizuya-Oka and Shimozawa, 1991). Although there are more than seven known antagonists of BMP-4 in vertebrates (Balemans and Hul, 2002), we used Chordin to inhibit BMP-4 activity, because it binds BMP-4 with a high affinity (Piccolo et al, 1996). In addition, we previously identified a Xenopus homolog of Drosophila Tolloid closely related to BMP-1 (Tolloid/BMP-1), which is known to degrade Chordin (Piccolo et al 1997;Wardle et al, 1999;Blitz et al, 2000;Balemans and Hul, 2002), as a TH response gene in the X. laevis intestine (Shimizu et al, 2002).…”

“…Although there are more than seven known antagonists of BMP-4 in vertebrates (Balemans and Hul, 2002), we used Chordin to inhibit BMP-4 activity, because it binds BMP-4 with a high affinity (Piccolo et al, 1996). In addition, we previously identified a Xenopus homolog of Drosophila Tolloid closely related to BMP-1 (Tolloid/BMP-1), which is known to degrade Chordin (Piccolo et al 1997;Wardle et al, 1999;Blitz et al, 2000;Balemans and Hul, 2002), as a TH response gene in the X. laevis intestine (Shimizu et al, 2002). Here, we show that Chordin is transiently expressed during intestinal remodeling and, by using its protein in vitro, that BMP-4 plays important roles in the adult epithelial differentiation as a connective tissue signaling factor.…”

Two‐dimensional morphogen gradient in Xenopus: Boundary formation and real‐time transduction response

“…Therefore, the distribution of a morphogen in the extracellular medium and the initiation of morphogen response are not always correlated. This finding is because signaling by a morphogen can be regulated in the extracellular medium in many different ways, including morphogen cleavage or morphogen binding (Balemans and Van Hul, 2002;Beck et al, 2002;Giraldez et al, 2002;Fujise et al, 2003;Kirkpatrick et al, 2004;Birsoy et al, 2005). Our experiments determine the time required for the initiation of response, rather than that required for the spread of morphogen.…”

The TGF‐β pseudoreceptor gene Bambi is dispensable for mouse embryonic development and postnatal survival

“…Since BMP signaling plays important roles in skeletal development, and genetic inactivation of other endogenous Bmp inhibitors resulted in skeletal defects (e.g., Balemans et al, 2002), we examined skeletal preparations of newborn pups. Compared with wildtype littermates, Bambi del/del mutant mice didn't exhibit any obvious defect in the skeleton (data not shown).…”