Molecules in focus
Noggin

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Abstract

Metabologens initiate, promote and maintain morphogenesis and adult tissue homeostasis. Bone morphogenetic proteins (BMPs) which belong to the transforming growth factor-β (TGF-β) superfamily, represent a major class of metabologens that regulate ectoderm, mesoderm and endoderm derived tissue formation. In order to temporally and spatially control BMP initiated signaling cascades, a tight regulatory network is needed to maintain concinnity. There are a number of ways how BMP signaling can be inhibited or more likely be modified, among which the direct extracellular inhibition through cysteine-knot containing proteins from the DAN-, the twisted gastrulation-, chordin- and noggin-family is a classic. This review focuses on noggin and its impact on the vast array of BMP driven actions and thereby invites the ever-growing BMP research field to (re-) investigate noggin's function in detail.

Introduction

Noggin, encoded by the NOG gene, is a secreted homodimeric glycoprotein with a molecular mass of 64 kDa. Noggin was discovered by its ability to induce secondary axis formation in Xenopus embryos (Smith and Harland, 1992). Noggin rescues dorsal development in UV-induced ventralized Xenopus embryos and injection of the putative cDNA results in excessive head development, hence the name noggin (Smith and Harland, 1992). Nowadays, noggin is known to regulate a major class of metabologens, so-called bone morphogenetic proteins (BMPs). It is suggested that due to excessive BMP action noggin null mice display serious developmental abnormalities (McMahon et al., 1998, Tylzanowski et al., 2006).

Section snippets

Structure

Noggin's primary structure consists of an acidic amino-terminal and a cysteine-rich carboxy-terminal region. Through the formation of cystine knots, the carboxy-terminal region is used to classify BMP antagonists into three distinct subfamilies: CAN (eight-membered ring), twisted gastrulation (nine-membered ring) as well as chordin and noggin (ten-membered ring) (Avsian-Kretchmer and Hsueh, 2004).

The topology of noggin resembles BMPs in a two-fold axis of symmetry. The BMP-dimer is shaped like

Expression, activation and turnover

Noggin is a pleiotropic factor, which is expressed both early in development as well as in later stages. During early gastrulation noggin is produced by the Spemann organizer and antagonizes the action of BMP-2, -4, -7, leading to a BMP gradient directed dorsal–ventral patterning with subsequent germ layer formation (Fig. 2) (Smith and Harland, 1992, Zimmerman et al., 1996).

Biological function

With the growing knowledge on BMPs and their respective tissue targets, the understanding of noggin's functionality is also strengthened (Table 1). In noggin null mice augmented BMP activity evokes a series of developmental abnormalities which include failure of neural tube formation, hair-follicle retardation, dysmorphogenesis of the axial skeleton and joint lesions (McMahon et al., 1998, Tylzanowski et al., 2006). Since noggin null mice are embryonic lethal, the role of noggin in adult tissue

Noggin's affinity to BMPs

Since Groppe and co-workers published the crystal structure of the BMP-7/noggin complex, a series of noggin point mutations was engineered to evaluate their respective binding affinities to BMP-7. Three noggin mutations (L46D, E48K and I218E) revealed lower BMP-7 binding affinities compared to wild type noggin, leading vice versa to the idea of tailored noggin-insensitive and thus more potent BMPs (Fig. 1) (Groppe et al., 2002). Since the binding sites for BMP type I and BMP type II receptors

Acknowledgments

This work was supported by the German Science Foundation (SFB 760, to P.K.). A.G. is a member of the Berlin-Brandenburg School for Regenerative Therapies (BSRT; GSC 230).

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