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BMPs inhibit neurogenesis by a mechanism involving degradation of a transcription factor

Nature Neuroscience volume 2, pages 339–345 (1999)Cite this article

Abstract

Bone morphogenetic proteins (BMPs), negative regulators of neural determination in the early embryo, were found to be potent inhibitors of neurogenesis in olfactory epithelium (OE) cultures. BMPs 2, 4 or 7 decreased the number of proliferating progenitor cells and blocked production of olfactory receptor neurons (ORNs). Experiments suggested that this effect was due to an action of BMPs on an early-stage progenitor in the ORN lineage. Further analysis revealed that progenitors exposed to BMPs rapidly (< 2 h) lost MASH1, a transcription factor known to be required for the production of ORNs. This disappearance was due to proteolysis of existing MASH1 protein, but new gene expression was required to trigger it. The data suggest a novel mechanism of BMP action, whereby the induced degradation of an essential transcription factor results in premature termination of a neuronal lineage.

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Figure 1: Inhibition of neuronal colony formation requires early addition of BMP4.
Figure 2: Effects of BMP4 on OE neuronal progenitor cells and ORNs.
Figure 3: BMP4 causes a rapid decrease in MASH1 immunoreactivity in OE neuronal progenitors.
Figure 4: BMP-mediated decrease in MASH1 immunoreactivity is due to loss of MASH1 protein.
Figure 5: MASH1 degradation is via proteasome-mediated proteolysis; downregulation of MASH1 immunoreactivity by BMP4 is dependent on transcription and translation.

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Acknowledgements

The authors are grateful to Youn Kim for help with experiments, and to Arthur Lander for suggestions regarding these studies. We thank Genetics Institute for the gift of recombinant human BMPs, Richard Harland for the gift of recombinant Xenopus noggin, David Anderson for anti-MASH1 hybridoma and Frank Solomon for rabbit antiserum to β-tubulin. This work was supported by a grant to A.L.C. from the Institute on Deafness and Other Communication Disorders of the N.I.H. (DC03583).

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  1. Department of Anatomy & Neurobiology and the Developmental Biology Center, 364 Med Surge II, University of California Irvine, College of Medicine, Irvine, 92697-1275 , California, USA

    Jianyong Shou, Peter C. Rim & Anne L. Calof

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Correspondence to Anne L. Calof.

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Shou, J., Rim, P. & Calof, A. BMPs inhibit neurogenesis by a mechanism involving degradation of a transcription factor. Nat Neurosci 2, 339–345 (1999). https://doi.org/10.1038/7251

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