Functional analysis of mammalian members of the transforming growth factor-beta superfamily

M M Matzuk1

  • 1The Departments of Pathology, Cell Biology, and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Insights

Gene targeting in mice reveals essential roles for transforming growth factor-beta (TGF-beta) superfamily members in development and disease. These studies uncover new functions for growth factors in mammals.

Area of Science:

  • Developmental Biology
  • Genetics
  • Molecular Biology

Background:

  • Growth factor function is studied in vitro and in vivo.
  • Gene targeting in embryonic stem (ES) cells is a powerful tool to evaluate protein roles.
  • The transforming growth factor-beta (TGF-beta) superfamily plays crucial roles in biological processes.

Purpose of the Study:

  • To review studies on the generation and analysis of mice deficient in TGF-beta superfamily members.
  • To highlight the insights gained from these studies into growth factor functions.
  • To emphasize the importance of TGF-beta superfamily members in mammalian biology.

Main Methods:

  • Gene targeting (knockout) strategies in ES cells.
  • Analysis of mice deficient in specific TGF-beta superfamily genes (e.g., TGF-beta1, MIS, inhibin alpha, activin betaA, activin betaB).
  • Identification and analysis of naturally occurring mouse mutants (short ear, brachypodism, insertional mutant 413-d) linked to specific loci (BMP-5, GDF-5, nodal).

Main Results:

  • Successful generation and analysis of mice deficient in various TGF-beta superfamily members.
  • Identification of mutations in BMP-5, GDF-5, and nodal loci in specific mouse mutants.
  • Demonstration of critical roles for these gene products in vivo.

Conclusions:

  • Studies on gene-targeted mice have provided critical insights into TGF-beta superfamily functions.
  • Members of the TGF-beta superfamily are essential for mammalian development.
  • These growth factors are also implicated in reproduction and oncogenesis.

Related Concept Videos

TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
General Transcription Factors01:30

General Transcription Factors

Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
Transcription Factors02:16

Transcription Factors

Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...
Canonical Wnt Signaling Pathway02:54

Canonical Wnt Signaling Pathway

The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which results in tumor...
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...