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

Abstract

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.

The BMP signaling and in vivo bone formation

“…Injection of BMP-2 locally over the surface of calvariae of mice induces periosteal bone formation without a prior cartilage phase (Chen et al, 1997b). Bmpr1a is widely expressed in a variety of tissues during development and in multiple adult tissues (Dewulf et al, 1995). In contrast, expression of Bmpr1b is restricted in early mesenchymal cells and differentiated chondrocytes (Ashique et al, 2002).…”

Mice lacking smooth muscle calponin display increased bone formation that is associated with enhancement of bone morphogenetic protein responses

“…In this process, the BMPs play an important role in the initiation of cartilage formation from mesenchymal condensation (Dewulf et al 1995;EnomotoIwamoto et al 1998). Double staining of embryos with Alizarin red and Alcian blue revealed that both cartilage formation (13.0 and 13.5 dpc) (Fig.…”

BMP controls nitric oxide-mediated regulation of cell numbers in the developing neural tube

“…First, the pattern of expression of bmpr-1a and bmpr-1b in the CNS of mouse embryos suggests that they have distinct roles in the transduction of BMP signal. 32,33 Second, while BMPR-IA is expressed ubiquitously in the NT and promotes BrdU incorporation into the CNS precursor cells, BMPR-IB is restricted to the dorsal NT where BMP is produced. In the dorsal NT, BMP limits precursor cell numbers by causing mitotic arrest, and consequently apoptosis in early gestation and terminal differentiation at mid-gestation embryos.…”