Tgfbeta signaling in growth control, cancer, and heritable disorders

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Bone morphogenetic proteins: multifunctional regulators of vertebrate development.

The Turing, or reaction-diffusion (RD), model is one of the best-known theoretical models used to explain self-regulated pattern formation in the developing animal embryo. Although its real-world relevance was long debated, a number of compelling examples have gradually alleviated much of the skepticism surrounding the model. The RD model can generate a wide variety of spatial patterns, and mathematical studies have revealed the kinds of interactions required for each, giving this model the potential for application as an experimental working hypothesis in a wide variety of morphological phenomena. In this review, we describe the essence of this theory for experimental biologists unfamiliar with the model, using examples from experimental studies in which the RD model is effectively incorporated.

https://science.sciencemag.org/content/sci/329/5999/1616.full.pdf

Reaction-diffusion model as a framework for understanding biological pattern formation

beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin.

Hair has many useful biologic functions, including protection from the elements and dispersion of sweat-gland products (e.g., pheromones). It also has psychosocial importance in our society, and patients with hair loss (alopecia) (Table 1) or excessive hair growth often suffer tremendously. Not surprisingly, the demand for drugs that alter hair growth and appearance has led to a multibillion-dollar industry, yet few drugs that are effective for these purposes are available. However, recent progress in our understanding of the biology and pathology of hair follicles should lead to more effective therapies for disorders of hair growth. Structure and Function of Hair . . .

The biology of hair follicles.

Local inhibitory action of BMPs and their relationships with activators in feather formation: implications for periodic patterning.

Mutations in GDF-5, a member of the TGF-beta superfamily, result in the autosomal recessive syndromes brachypod (bp) in mice and Hunter-Thompson and Grebe-type chondrodysplasias in humans. These syndromes are all characterised by the shortening of the appendicular skeleton and loss or abnormal development of some joints. To investigate how GDF-5 controls skeletogenesis, we overexpressed GDF-5 during chick limb development using the retrovirus, RCASBP. This resulted in up to a 37.5% increase in length of the skeletal elements, which was predominantly due to an increase in the number of chondrocytes. By injecting virus at different stages of development, we show that GDF-5 can increase both the size of the early cartilage condensation and the later developing skeletal element. Using in vitro micromass cultures as a model system to study the early steps of chondrogenesis, we show that GDF-5 increases chondrogenesis in a dose-dependent manner. We did not detect changes in proliferation. However, cell suspension cultures showed that GDF-5 might act at these stages by increasing cell adhesion, a critical determinant of early chondrogenesis. In contrast, pulse labelling experiments of GDF-5-infected limbs showed that at later stages of skeletal development GDF-5 can increase proliferation of chondrocytes. Thus, here we show two mechanisms of how GDF-5 may control different stages of skeletogenesis. Finally, our data show that levels of GDF-5 expression/activity are important in controlling the size of skeletal elements and provides a possible explanation for the variation in the severity of skeletal defects resulting from mutations in GDF-5.

Mechanisms of GDF-5 action during skeletal development.

Overexpression of BMP-2 and BMP-4 alters the size and shape of developing skeletal elements in the chick limb

Bone morphogenetic protein-2 (BMP-2) has been implicated in the polarizing region signalling pathway, which specifies pattern across the antero-posterior of the developing vertebrate limb. Retinoic acid and Sonic Hedgehog (SHH) can act as polarizing signals; when applied anteriorly in the limb bud, they induce mirror-image digit duplications and ectopic Bmp-2 expression in anterior mesenchyme. In addition, the two signals can activate Fgf-4 expression in anterior ridge and HoxD expression in anterior mesenchyme. We tested the role of BMP-2 in this signalling cascade by ectopically expressing human BMP-2 (hBMP-2) at the anterior margin of the early wing bud using a replication defective retroviral vector, and found that ectopic expression of Fgf-4 was induced in the anterior part of the apical ectodermal ridge, followed later by ectopic expression of Hoxd-11 and Hoxd-13 in anterior mesenchyme. This suggests that BMP-2 is involved in regulating Fgf-4 and HoxD gene expression in the normal limb bud. Ectopically expressed hBMP-2 also induced duplication of digit 2 and bifurcation of digit 3, but could not produce the mirror-image digit duplications obtained with SHH-expressing cells. These results suggest that BMP-2 may be involved primarily in maintenance of the ridge, and in the link between patterning and outgrowth of the limb bud.

Activation of Fgf-4 and HoxD gene expression by BMP-2 expressing cells in the developing chick limb.

Bone morphogenetic proteins BMP-4 and BMP-2 are closely-related members of the transforming growth factor-beta superfamily that have been implicated in signalling in a number of developmental systems. To determine whether they could be involved in the epithelial-mesenchymal interactions that control face development, we mapped the distribution of Bmp-4 and Bmp-2 gene transcripts in the developing chick facial primordia. At stages when primordia were becoming established, Bmp-4 transcripts were present in specific regions of epithelium in all facial primordia, but were undetectable in the mesenchyme. Bmp-4 transcripts appeared subsequently in specific regions of mesenchyme at the distal tips of the primordia. This mesenchymal expression first appeared in the frontonasal mass and then, in turn, in the lateral nasal processes, the maxillary primordia and the mandibular primordia. There was a complex relationship between domains of epithelial and mesenchymal Bmp-4 expression, and at many sites there was an inverse correlation between epithelial and mesenchymal Bmp-4 expression. Bmp-2 transcripts were found in the epithelium and mesenchyme of the maxillary and mandibular primordia at early stages in facial development. Bmp-2 transcripts appeared in the frontonasal mass and lateral nasal processes at later stages, with epithelial expression preceding mesenchymal expression. In general, mesenchymal Bmp-2 expression was associated with overlying epithelial Bmp-2 expression. The domains of Bmp-4 expression overlapped with those of Bmp-2, but detailed examination showed that there was no precise correlation between the expression patterns of the two genes. Indeed, in some places the Bmp-4 and Bmp-2 expression domains were complementary. The expression of the Bmp-4 and Bmp-2 genes in the epithelium and distal mesenchyme of the facial primordia suggests that BMP-4 and BMP-2 may be involved in the epithelial-mesenchymal interactions that control outgrowth of these primordia.

https://anatomypubs.onlinelibrary.wiley.com/doi/pdf/10.1002/aja.1002010207

Philippa H. Francis-West

Papers

Local inhibitory action of BMPs and their relationships with activators in feather formation: implications for periodic patterning.

Mechanisms of GDF-5 action during skeletal development.

Overexpression of BMP-2 and BMP-4 alters the size and shape of developing skeletal elements in the chick limb

Activation of Fgf-4 and HoxD gene expression by BMP-2 expressing cells in the developing chick limb.

Expression patterns of the bone morphogenetic protein genes Bmp-4 and Bmp-2 in the developing chick face suggest a role in outgrowth of the primordia