Distinct spatial and temporal expression patterns of two type I receptors for bone morphogenetic proteins during mouse embryogenesis.

Bone morphogenetic proteins (BMPs) are multifunctional proteins structurally related to transforming growth factor-beta (TGF beta) and activin that can induce cartilage and bone growth in vivo. Members of the TGF beta superfamily exert their biological effects via heteromeric serine/threonine kinase complexes of type I and type II receptors. We previously obtained six different type I receptors, termed activin receptor-like kinase-1 (ALK-1) to -6. ALK-5 is a TGF beta type I receptor, ALK-2 and ALK-4 are activin type I receptors, and ALK-3 and ALK-6 are type I receptors for osteogenic protein-1 (OP-1)/bone morphogenetic protein-7 (BMP-7) and BMP-4. Here we report the complementary DNA cloning of the mouse homolog of ALK-3, which is highly conserved between mouse and man. ALK-3 messenger RNA (mRNA) is ubiquitously expressed in various adult mouse tissues, whereas ALK-6 mRNA is only found in brain and lung. The distribution of ALK-3 and ALK-6 mRNA in the postimplantation mouse embryo [6.5-15.5 days postcoitum (pc)] was studied by in situ hybridization. ALK-3 was nearly ubiquitously expressed throughout these stages of development, but was notably absent in the liver. In contrast, ALK-6 showed a more restricted expression pattern. ALK-6 mRNA was absent in early postimplantation embryos, was detected first in 9.5 days pc embryos, and persisted until 15.5 days pc. In midgestation embryos, ALK-6 transcripts were detected in mesenchymal precartilage condensations, premuscle masses, blood vessels, central nervous system, parts of the developing ear and eye, and epithelium. The expression in sites of developing cartilage and bone supports the idea that ALK-3 and -6 are receptors for BMPs in vivo. In addition, the expression of these genes in many soft tissues suggests broader functions for BMPs in embryogenesis.

[1]  J. Massagué,et al.  Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells , 1994, Molecular and Cellular Biology.

[2]  R. Tizard,et al.  Cloning, expression, and alternative splicing of the receptor for anti-Müllerian hormone. , 1994, Molecular endocrinology.

[3]  J. Massagué,et al.  Identification of two bone morphogenetic protein type I receptors in Drosophila and evidence that Brk25D is a decapentaplegic receptor , 1994, Cell.

[4]  D. Riddle,et al.  Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. , 1994, The Journal of biological chemistry.

[5]  J. Massagué,et al.  Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin , 1994, Molecular and cellular biology.

[6]  N. Copeland,et al.  Limb alterations in brachypodism mice due to mutations in a new member of the TGFβ-superfamily , 1994, Nature.

[7]  K. Miyazono,et al.  Characterization of type I receptors for transforming growth factor-beta and activin. , 1994, Science.

[8]  J. Massagué,et al.  Two distinct transmembrane serine/threonine kinases from Drosophila melanogaster form an activin receptor complex , 1994, Molecular and cellular biology.

[9]  J. Slack.  Inducing factors in Xenopus early embryos , 1994, Current Biology.

[10]  L. Wilming,et al.  A novel member of the transmembrane serine/threonine kinase receptor family is specifically expressed in the gonads and in mesenchymal cells adjacent to the müllerian duct. , 1994, Development.

[11]  J. Massagué,et al.  Identification of human activin and TGFβ type I receptors that form heteromeric kinase complexes with type II receptors , 1993, Cell.

[12]  K. Miyazono,et al.  Cloning of a TGFβ type I receptor that forms a heteromeric complex with the TGFβ type II receptor , 1993, Cell.

[13]  K. Miyazono,et al.  Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. , 1993, Oncogene.

[14]  P. Schnegelsberg,et al.  Osteogenic protein-2. A new member of the transforming growth factor-beta superfamily expressed early in embryogenesis. , 1992, The Journal of biological chemistry.

[15]  Jeffrey L. Wrana,et al.  TGFβ signals through a heteromeric protein kinase receptor complex , 1992, Cell.

[16]  N. Copeland,et al.  The mouse short ear skeletal morphogenesis locus is associated with defects in a bone morphogenetic member of the TGFβ superfamily , 1992, Cell.

[17]  V. Rosen,et al.  The BMP proteins in bone formation and repair. , 1992, Trends in genetics : TIG.

[18]  M. Sporn,et al.  The Transforming Growth Factor-βs , 1991 .

[19]  F. Sanger,et al.  DNA sequencing with chain-terminating inhibitors. , 1977, Proceedings of the National Academy of Sciences of the United States of America.