Glenn E. Winnier

A mouse homologue of FAST-1 transduces TGFβ superfamily signals and is expressed during early embryogenesis

The transcription factor FAST-1 has recently been shown to play a key role in the specification of mesoderm by TGF beta superfamily signals in the early Xenopus embryo. We have cloned Fast1, a mouse homologue of Xenopus FAST-1, and characterized its expression during embryogenesis and function in activin/TGF beta signal transduction. In vitro, Fast1 associates with Smads in response to an activin/TGF beta signal to form a complex that recognizes the Xenopus activin responsive element (ARE) targeted by Xenopus FAST-1. In intact cells, introduction of Fast1 confers activin/TGF beta regulation of an ARE-luciferase reporter. In embryos, Fast1 is expressed predominantly throughout the epiblast before gastrulation and declines as development progresses. We propose that mouse Fast1, like Xenopus FAST-1, mediates TGF beta superfamily signals specifying developmental fate during early embryogenesis.

Mouse Mesenchyme forkhead 2 (Mf2): expression, DNA binding and induction by sonic hedgehog during somitogenesis

Cloning and sequencing of mouse Mf2 (mesoderm/mesenchyme forkhead 2) cDNAs revealed an open reading frame encoding a putative protein of 492 amino acids which, after in vitro translation, binds to a DNA consensus sequence. Mf2 is expressed at high levels in the ventral region of newly formed somites, in sclerotomal derivatives, in lateral plate and cephalic mesoderm and in the first and second branchial arches. Other regions of mesodermal expression include the developing tongue, meninges, nose, whiskers, kidney, genital tubercule and limb joints. In the nervous system Mf2 is transcribed in restricted regions of the mid- and forebrain. In several tissues, including the early somite, Mf2 is expressed in cell populations adjacent to regions expressing sonic hedgehog (Shh) and in explant cultures of presomitic mesoderm Mf2 is induced by Shh secreted by COS cells. These results suggest that Mf2, like other murine forkhead genes, has multiple roles in embryogenesis, possibly mediating the response of cells to signaling molecules such as SHH.

EVIDENCE FROM NORMAL EXPRESSION AND TARGETED MISEXPRESSION THAT BONE MORPHOGENETIC PROTEIN-4 (BMP-4) PLAYS A ROLE IN MOUSE LUNG MORPHOGENESIS.|[bull]| 1992

Epithelial-mesenchymal interactions are critical for the branching and differentiation of the lung, but the mechanisms involved are still unclear. To investigate this problem in mouse embryonic lung we have studied the temporal and spatial expression of factors implicated in the morphogenesis of other organs. At 11.5 days post coitum (p.c.) hepatocyte nuclear factor-3β (HNF-3β) is expressed uniformly throughout the epithelium; whereas Wnt-2 expression is confined to the distal mesenchyme. Sonic hedgehog (Shh) transcripts are found at low levels throughout the epithelium but at high levels in the distal tips of the terminal buds. Epithelial expression is also seen for bone morphogenetic protein-7 (Bmp-7), but transcripts are less dramatically upregulated at the distal tips. The Type I Bone morphogenetic protein receptor (Bmpr/TFR-11, Brk-1) is expressed at low levels in the epithelium and in the distal mesenchyme. Finally, Bmp-4 transcripts are localized at high levels in the distal tips of the epithelium and in the adjacent mesenchyme. To study further the role of Bmp-4 in lung development, we have misexpressed the gene throughout the distal epithelium of transgenic embryos using a surfactant protein C enhancer/promoter. From 15.5 days p.c. transgenic lungs are smaller than normal, with grossly distended terminal buds, and at birth, contain large airfilled sacs which do not support normal lung function. Labeling with bromodeoxyuridine reveals an inhibition of epithelial proliferation in 15.5 days p.c. transgenic lungs. A small but significant stimulation of proliferation of mesenchymal cells is also observed, but this is accompanied by an increase in apoptosis. In situ hybridization with riboprobes for the proximal airway marker, CC10, and the distal airway marker, SP-C, shows normal differentiation of bronchiolar Clara cells but a reduction in the number of differentiated Type II cells in transgenic lungs. A model is proposed for the role of Bmp-4 and other signalling molecules in embryonic lung morphogenesis