Sequential actions of BMP receptors control neural precursor cell production and fate.
Journal: 2001/September - Genes and Development
ISSN: 0890-9369
Abstract:
Bone morphogenetic proteins (BMPs) have diverse and sometimes paradoxical effects during embryonic development. To determine the mechanisms underlying BMP actions, we analyzed the expression and function of two BMP receptors, BMPR-IA and BMPR-IB, in neural precursor cells in vitro and in vivo. Neural precursor cells always express Bmpr-1a, but Bmpr-1b is not expressed until embryonic day 9 and is restricted to the dorsal neural tube surrounding the source of BMP ligands. BMPR-IA activation induces (and Sonic hedgehog prevents) expression of Bmpr-1b along with dorsal identity genes in precursor cells and promotes their proliferation. When BMPR-IB is activated, it limits precursor cell numbers by causing mitotic arrest. This results in apoptosis in early gestation embryos and terminal differentiation in mid-gestation embryos. Thus, BMP actions are first inducing (through BMPR-IA) and then terminating (through BMPR-IB), based on the accumulation of BMPR-IB relative to BMPR-IA. We describe a feed-forward mechanism to explain how the sequential actions of these receptors control the production and fate of dorsal precursor cells from neural stem cells.
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Genes Dev 15(16): 2094-2110

Sequential actions of BMP receptors control neural precursor cell production and fate

Laboratory of Molecular Biology, NINDS, National Institutes of Health, Bethesda, Maryland 20892-4092, USA; Laboratory of Stem Cell and Tumor Biology, Neurosurgery and Cellular Biochemistry and Biophysics, Memorial Sloan Kettering Cancer Center; New York, New York 10021, USA
Present address: Department of Biochemistry, College of Medicine, Hanyang University, Haengdang-dong, Sungdong-ku, 133-791, Seoul, South Korea;
Present address: University of Maryland Biotechnology Institute, University of Maryland—Baltimore County, Baltimore, MD 21201, USA;
Present address: NeuralStem Biopharmaceuticals, Bethesda, MD 20817, USA.
Corresponding author.
Received 2001 Mar 9; Accepted 2001 Jun 19.

Abstract

Bone morphogenetic proteins (BMPs) have diverse and sometimes paradoxical effects during embryonic development. To determine the mechanisms underlying BMP actions, we analyzed the expression and function of two BMP receptors, BMPR-IA and BMPR-IB, in neural precursor cells in vitro and in vivo. Neural precursor cells always express Bmpr-1a, but Bmpr-1b is not expressed until embryonic day 9 and is restricted to the dorsal neural tube surrounding the source of BMP ligands. BMPR-IA activation induces (and Sonic hedgehog prevents) expression of Bmpr-1b along with dorsal identity genes in precursor cells and promotes their proliferation. When BMPR-IB is activated, it limits precursor cell numbers by causing mitotic arrest. This results in apoptosis in early gestation embryos and terminal differentiation in mid-gestation embryos. Thus, BMP actions are first inducing (through BMPR-IA) and then terminating (through BMPR-IB), based on the accumulation of BMPR-IB relative to BMPR-IA. We describe a feed-forward mechanism to explain how the sequential actions of these receptors control the production and fate of dorsal precursor cells from neural stem cells.

Keywords: Bone morphogenetic protein, receptor, neural, development, precursor cell
Abstract

Animal development involves a complex progression of tissue induction and morphogenesis, expansion of precursor cell populations, and the death or terminal differentiation of these cells into specific functional types. Bone morphogenetic protein (BMP) signaling is repeatedly used in this dynamic process for both vertebrates and invertebrates. In gastrulating Xenopus and Drosophila, BMPs and the BMP2/4 homolog Decapentaplegic (Dpp) contribute to specifying the embryonic dorsoventral axis. High activity of BMP/Dpp induces blood/amnioserosa, whereas maximal inhibition of BMP/Dpp leads to neural ectoderm induction (Dale 2000; Nakayama et al. 2000). Subsequently, BMP/Dpp signaling contributes to the specification and/or expansion of many tissues such as vertebrate limb and Drosophila wing (Vogt and Duboule 1999; Day and Lawrence 2000) and neural ectoderm (Cornell and Ohlen 2000).

Vertebrate neural ectoderm undergoes a period of rapid proliferation and morphogenetic movements to form a neural tube, as signals from adjacent tissues induce dorsal–ventral and anterior-posterior identities on precursors (Altmann and Brivanlou 2001). BMPs are expressed at high levels in nonneural ectoderm and then in the roof plate of the neural tube (Liem et al. 1995; Furuta et al. 1997). A BMP activity gradient induces dorsal identity markers indicative of neural crest or dorsal interneuron precursors (Liem et al. 1997; Nguyen et al. 1998, 2000; Barth et al. 1999). However, BMPs also cause apoptosis in early central nervous system (CNS) precursor cells (Graham et al. 1996; Furuta et al. 1997), neuronal differentiation in mid-gestation CNS precursors (Li et al. 1998; Mehler et al. 2000), and glial differentiation in late embryonic or adult CNS precursors (Gross et al. 1996).

It is unclear how BMPs mediate such a wide variety of responses, but it may be a result of diversity in the components of signal transduction. Some BMP-related ligands are known to be involved in the generation of specific cell types (Shah et al. 1996; Lee et al. 1998), but there is evidence that many act in a redundant manner (Dudley and Robertson 1997; Solloway et al. 1998; Zhao et al. 1999). BMPs exert their effects by activating a complex of type I and type II receptors. The type II receptor is the primary ligand-binding component; both BMPRII and ActRIIB are functional type II receptors for BMPs. Type I receptors also have BMP-binding properties but are primarily responsible for transducing the signal into the cell: BMPR-IA (Alk3), BMPR-IB (Alk6), and ActR-I (Alk2) are all known to transduce BMP signals (Kawabata et al. 1998). The activated type I receptors in turn phosphorylate the DNA-binding proteins Smad1, Smad5, and Smad8, each of which can then heteromerize with Smad4 and translocate to the nucleus to regulate transcription of downstream target genes (Itoh et al. 2000).

The expression patterns of Bmpr-1a and Bmpr-1b in the CNS (Dewulf et al. 1995; Zhang et al. 1998) suggest that they have distinct roles in the transduction of BMP signals. In an effort to understand their role in neural development, we used multipotent CNS stem cells as a defined system to understand signals that control proliferation and fate choice (Johe et al. 1996; Studer et al. 1998). We have also developed a vector using POU-regulated genomic elements that control expression of the intermediate filament gene nestin in CNS precursor cells (Josephson et al. 1998). This vector, called pNERV, expresses mutant BMP receptors selectively in CNS stem cells in vitro and in transgenic mice. Using these tools, we show that most of the known actions of BMPs during neural precursor development can be attributed to the distinct actions of BMPR-IA and BMPR-IB. Furthermore, the activities of these receptors are linked sequentially, with BMPR-IA acting first and inducing the expression of Bmpr-1b. These results identify a feed-forward mechanism by which BMPs can control both the production and fate of precursor cells.

Acknowledgments

We would like to thank Dr. Lee Niswander for her generous gift of the mutant Bmpr-1a and Bmpr-1b constructs. BMP2 was supplied by agreement with Genetics Institute. Activated Caspase3 antibody (CM1) was supplied by agreement with Idun Pharmaceuticals. Monoclonal antibodies for Pax7 (from Dr. A. Kawakami) and Islet1 (40.2D6 from Dr. T. Jessell) were obtained from the Developmental Studies Hybridoma Bank. We are grateful for the gift of Pax6 antibody from Dr. Randall Reed and cyclopamine from Dr. William Gaffield). We also thank Dr. James Nagle of the NINDS DNA-sequencing facility for sequence verification of constructs; Drs. Heather Cameron and Susan Wray for technical advice; and Dr. Martin Sailer, Helen Mitchell, Michael Nguyen, Emily Liu, and Martha Kimos for excellent technical assistance.

The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 USC section 1734 solely to indicate this fact.

Acknowledgments

Footnotes

E-MAIL vog.hin.nodoc@yakcm; FAX (301) 402-1340.

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.894701.

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