Members of the TGF-beta superfamily, which includes TGF-betas, growth differentiation factors, bone morphogenetic proteins, activins, inhibins, and glial cell line-derived neurotrophic factor, are synthesized as prepropeptide precursors and then processed and secreted as homodimers or heterodimers. Most ligands of the family signal through transmembrane serine/threonine kinase receptors and SMAD proteins to regulate cellular functions. Many studies have reported the characterization of knockout and knock-in transgenic mice as well as humans or other mammals with naturally occurring genetic mutations in superfamily members or their regulatory proteins. These investigations have revealed that TGF-beta superfamily ligands, receptors, SMADs, and upstream and downstream regulators function in diverse developmental and physiological pathways. This review attempts to collate and integrate the extensive body of in vivo mammalian studies produced over the last decade.

/pdf/genetic-analysis-of-the-mammalian-transforming-growth-factor-3c5w7hm58x.pdf

Genetic analysis of the mammalian transforming growth factor-beta superfamily.

Trophoblasts, the specialized cells of the placenta, play a major role in implantation and formation of the maternal-fetal interface. Through an unusual differentiation process examined in this review, these fetal cells acquire properties of leukocytes and endothelial cells that enable many of their specialized functions. In recent years a great deal has been learned about the regulatory mechanisms, from transcriptional networks to oxygen tension, which control trophoblast differentiation. The challenge is to turn this information into clinically useful tests for monitoring placental function and, hence, pregnancy outcome.

/pdf/trophoblast-differentiation-during-embryo-implantation-and-3kto5bm947.pdf

Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface

Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.

Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma

Elimination of the developing female reproductive tract in male fetuses is an essential step in mammalian sexual differentiation1. In males, the fetal testis produces the transforming growth factor β (TGF-β) family member anti-Mullerian hormone (Amh, also known as Mullerian-inhibiting substance (Mis)), which causes regression of the Mullerian ducts, the primordia of the oviducts, uterus and upper vagina2. Amh induces regression by binding to a specific type II receptor (Amhr2) expressed in the mesenchyme surrounding the ductal epithelium3,4,5,6,7. Mutations in AMH or AMHR2 in humans and mice disrupt signaling, producing male pseudohermaphrodites that possess oviducts and uteri8,9,10. The type I receptor and Smad proteins that are required in vivo for Mullerian duct regression have not yet been identified11,12,13,14. Here we show that targeted disruption of the widely expressed type I bone morphogenetic protein (BMP) receptor Bmpr1a (also known as Alk3) in the mesenchymal cells of the Mullerian ducts leads to retention of oviducts and uteri in males. These results identify Bmpr1a as a type I receptor for Amh-induced regression of Mullerian ducts. Because Bmpr1a is evolutionarily conserved, these findings indicate that a component of the BMP signaling pathway has been co-opted during evolution for male sexual development in amniotes.

Requirement of Bmpr1a for Müllerian duct regression during male sexual development.

During the past two decades, a significant amount of data has been accumulated revealing the intriguing functions of bone morphogenetic proteins (BMPs) in all aspects of embryonic development and organogenesis. Numerous genes encoding BMPs, BMP receptors, and their downstream signal transducers have been mutated in the mouse through targeted mutagenesis. This review focuses on what is known about the role of BMP signaling in gastrulation, mesoderm formation, left-right asymmetry, neural patterning, skeletal and limb development, organogenesis, and gametogenesis as revealed by BMP-signaling mutants.

Consequences of knocking out BMP signaling in the mouse

Multiple roles for activin-like kinase-2 signaling during mouse embryogenesis.

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Multiple roles for activin-like kinase-2 signaling during mouse embryogenesis.