The mammalian twisted gastrulation gene functions in foregut and craniofacial development

Abstract

Extracellular modulators of cell-cell signaling control numerous aspects of organismal development. The Twisted gastrulation (Twsg1) gene product is a small, secreted cysteine-rich protein that has the unusual property of being able to either enhance or inhibit signaling by the bone morphogenetic protein (BMP) subfamily of TGF-beta type factors in a context-dependent manner. In this report, we characterize the early embryonic and skeletal phenotypes associated with loss of Twsg1 function in mice. All Twsg1 mutant mice, irrespective of genetic background, exhibit deletions of neural arches in the cervical vertebrae. In a C57BL/6 background, we also observe pronounced forebrain defects including rostral truncations, holoprosencephaly, cyclopia, as well as alterations in the first branchial arch (BA1) leading to lack of jaw (agnathia). Characterization of marker expression suggests that these defects are attributable to loss of signaling from forebrain-organizing centers including Fgf8 from the anterior neural ridge (ANR) and Shh from the prechordal plate (PrCP). In addition, we find defects in the foregut endoderm and a reduction in Hex expression, which may contribute to both the forebrain and BA1 defects.

von Willebrand Factor Type C Domain-containing Proteins Regulate Bone Morphogenetic Protein Signaling through Different Recognition Mechanisms

“…Our result indicates that this inhibition must be enhanced by the presence of Tsg. Recent results from Tsg-deficient mice indicated a critical role of Tsg in skeletal development of vertebrates (47)(48)(49)(50). Tsg has also been shown to be an important modulator of BMP-regulated cartilage development and chondrocyte differentiation (51).…”

Chordin-like 1 and Twisted Gastrulation 1 Regulate BMP Signaling following Kidney Injury

“…31 Because the BMP-antagonistic properties of the related protein Chordin are, in some contexts, dependent on Twisted gastrulation as an accessory protein, 15,32,33 we included recombinant Twisted gastrulation homolog 1 (TWSG1) in our analysis. Surprisingly, CHRDL1 or Chordin alone amplified BMP4-induced signaling.…”

21st Century neontology and the comparative development of the vertebrate skull

“…Such loss of midline structures is in line with the loss of gene expression in both the distal midline of mdBA1 (Ptch1), ANR, and commissural plate (e.g., Fgf8 and BF1 [Foxg1]). Mice null for Twisted gastrulation (Twsg1), which is thought to act as a BMP inhibitor, also shows a similar range of midline truncations (Petryk et al, 2004). In similar manner, increased BMP signaling by means of application of ectopic BMP proteins to the anterior, ventral forebrain yields cyclopic chicks and reduces regional Shh and Fgf8 expression (Golden et al, 1999;Ohkubo et al, 2002).…”