Abstract
Bone morphogenetic proteins (BMPs) are considered important regulators of neural development. However, results mainly from a wide set of in vitro gain-of-function experiments are conflicting since these show that BMPs can act either as inhibitors or promoters of neurogenesis. Here, we report a specific and non-redundant role for BMP7 in cortical neurogenesis in vivo using knockout mice. Bmp7 is produced in regions adjacent to the developing cortex; the hem, meninges, and choroid plexus, and can be detected in the cerebrospinal fluid. Bmp7 deletion results in reduced cortical thickening, impaired neurogenesis, and loss of radial glia attachment to the meninges. Subsequent in vitro analyses of E14.5 cortical cells revealed that lack of Bmp7 affects neural progenitor cells, evidenced by their reduced proliferation, survival and self-renewal capacity. Addition of BMP7 was able to rescue these proliferation and survival defects. In addition, at the developmental stage E14.5 Bmp7 was also required to maintain Ngn2 expression in the subventricular zone. These data demonstrate a novel role for Bmp7 in the embryonic mouse cortex: Bmp7 nurtures radial glia cells and regulates fundamental properties of neural progenitor cells that subsequently affect Ngn2-dependent neurogenesis.
Highlights
Embryonic brain development is based on the sequential generation and differentiation of neuroepithelial precursor cells
BMP7 is necessary for the correct regulation of cortical plate size Corticogenesis is guided by a combination of transcription factors acting downstream of extrinsic cues that establish within the cortex the identity, delineation and size of its domains
This observation indicates that the Bmp7 produced in the choroid plexus could reach the ventricular zone through the cerebrospinal fluid (CSF)
Summary
Embryonic brain development is based on the sequential generation and differentiation of neuroepithelial precursor cells. Distinct areas may act as signalling centers that control these developmental steps. It has been well-established that Bone Morphogenetic Proteins (BMP) control neural development [2]. BMP signalling activity in vivo is highly regulated at several levels of the pathway, including extracellularly where secreted BMP-binding proteins like Noggin, Chordin, and Gremlin act as BMP antagonists [7]. Despite intensive research in the BMP field over the last 20 years the cell-type specific requirements for individual members of the BMP subgroup in complex tissue interactions during embryogenesis and organogenesis are still largely unknown
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