Abstract
Insights into Bone morphogenetic protein (Bmp) functions during forebrain development have been limited by a lack of Bmp signaling readouts. Here we used a novel Bmp signaling reporter (“BRE-gal” mice) to study Bmp signaling in the dorsal telencephalon. At early stages, BRE-gal expression was restricted to the dorsal telencephalic midline. At later stages, strong BRE-gal expression occurred in neurons of the marginal zone and dentate gyrus. Comparisons to nuclear phospho-Smad1/5/8 (pSmad) and Msx1 indicated that BRE-gal expression occurred exclusively in neural cells with high-level Bmp signaling. BRE-gal responsiveness to Bmps was confirmed in reporter-negative cortical cells cultured with Bmp4, and both in vivo and in vitro, BRE-gal expression was switch-like, or ultrasensitive. In the early dorsal telencephalon, BRE-gal expression negatively correlated with the cortical selector gene Lhx2, indicating a BRE-gal expression border that coincides with the cortex-hem boundary. However, in Lhx2 null chimeras, neither BRE-gal nor nuclear pSmad increases were observed in ectopic hem cells. These findings establish BRE-gal as an ultrasensitive reporter of Bmp signaling in the dorsal telencephalon, imply that hem fate can be specified at different Bmp signaling intensities, and suggest that Lhx2 primarily regulates the responses to – rather than the intensity of – Bmp signaling in dorsal telencephalic cells.
Highlights
Bone morphogenetic proteins (Bmps) are intimately involved in many nervous system processes, spanning from the induction of neuroectoderm to the maintenance of adult stem cells
We describe Bmp response element (BRE)-gal expression in marginal zone and dentate gyrus neurons, and find that neither BRE-gal activity nor high phospho-Smad1/ 5/8 (pSmad) levels are seen in ectopic hem cells in Lhx2-null chimeras, which suggests that cortical hem differentiation can occur at lower Bmp signaling intensities than those seen in the dorsal telencephalic midline (DTM), if Lhx2 is absent
BRE-gal expression is prominent in the DTM and in marginal zone neurons, at later stages in dentate gyrus (DG) granule neurons and certain pyramidal neurons of the hippocampus
Summary
Bone morphogenetic proteins (Bmps) are intimately involved in many nervous system processes, spanning from the induction of neuroectoderm to the maintenance of adult stem cells. Nuclear phosphorylated Smad1/5/8 (hereafter referred to as ‘‘pSmad’’) is a direct readout of Bmp signaling, but nuclear pSmad has limitations as a quantitative readout and does not report transcriptional activity. To overcome these limitations, other groups have generated Bmp reporter mice using a 47-bp Smad-binding enhancer (SBE) from the mouse Id1 gene [4,5,6]. Other groups have generated Bmp reporter mice using a 47-bp Smad-binding enhancer (SBE) from the mouse Id1 gene [4,5,6] In these mice, reporter expression in the dorsal telencephalon – our system of interest – has not been well characterized or appears weak to absent [4,5,6]
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