Elsevier

Neuroscience Research

Volume 41, Issue 4, 21 December 2001, Pages 391-396
Neuroscience Research

Fate alteration of neuroepithelial cells from neurogenesis to astrocytogenesis by bone morphogenetic proteins

https://doi.org/10.1016/S0168-0102(01)00297-8Get rights and content

Abstract

Bone morphogenetic proteins (BMPs), a class of cytokines belonging to the transforming growth factor-β superfamily, have been shown to play a wide variety of roles during development including those in the central nervous system. We here report that BMP2, BMP4 and BMP7 have an equivalent potential to inhibit neurogenesis and concomitantly induce astrocytogenesis of mouse fetal neuroepithelial cells. We further show that these BMPs activate a promoter of the gene for negative helix-loop-helix (HLH) factor, Id1, which is known to inhibit the function of such neurogenic transcription factors as Mash1 and neurogenin. These results suggest that BMP2, BMP4 and BMP7 alternate the fate of neuroepithelial cells from neuronal type to astrocytic one via a common mechanism involving negative HLH factor.

Introduction

The central nervous system is organized by neuronal and glial cells generated from common neural precursor cells during the development (McKay, 1997, Gage, 2000). The fate determination of the precursors is regulated by cell-intrinsic programs as well as extrinsic cues from surrounding environment. Bone morphogenetic proteins (BMPs) are known as such extrinsic cues.

BMPs are cytokines belonging to the transforming growth factor-β (TGF-β ) superfamily (Heldin et al., 1997, Massagué and Chen, 2000) and are known to signal through heterotetrameric serine/threonine kinase receptors comprising two type I and II receptor molecules. Activated receptors phosphorylate transcription factors called receptor-restricted Smads (Smad1, Smad5 and Smad8), which allows them to associate with a common mediator, Smad4, leading to transactivation of target genes. Although BMPs were initially identified for their osteoinductive property, they have been demonstrated to exhibit a wide variety of functions in the central and peripheral nervous system development (Gross et al., 1996, Li et al., 1998, Lim et al., 2000, Reissmann et al., 1996, Schneider et al., 1999, Shah et al., 1996, Shou et al., 1999, Shou et al., 2000). We have previously reported that BMP2 induces astrocytogenesis of fetal mouse neuroepithelial cells in cooperation with leukemia inhibitory factor (LIF), which is a member of the interleukin 6 (IL-6) family of cytokines (Nakashima et al., 1999b). These two cytokines act in synergy via complex formation of respective downstream transcription factors, Smad1 and signal transducer and activator of transcription 3 (STAT3), bridged by transcriptional coactivator, p300 (Nakashima et al., 1999b). Furthermore, we have revealed that not only BMP2 but also BMP4 and BMP7 induce synergistic astrocytogenesis with the IL-6 family of cytokines (Nakashima et al., 1999c, Ochiai et al., 2001, Yanagisawa et al., 2001). Quite recently, we further reported that BMP2 represses neurogenesis in cultured neuroepithelial cells, suggesting fate change effect of BMP2 on these cells (Nakashima et al., 2001).

It is well known that neurogenic basic helix-loop-helix (HLH) transcription factors such as Mash1 and neurogenin function in a heterodimeric form with a ubiquitously expressed basic HLH factor such as E12 and E47 (Kageyama and Nakanishi, 1997). Function of these neurogenic basic HLH factors is inhibited by competitive binding of negative regulatory HLH factors belonging to the Id and HES families to E12 and E47. We have clarified that BMP2-induced up-regulation of negative HLH factors mediates the repression of neurogenesis of neuroepithelial cells most likely by suppressing the function of neurogenic basic HLH factors (Nakashima et al., 2001). In the present study, we demonstrate that this effect is not confined to BMP2 but is generally observed with BMP4 and BMP7 as well, both of which are shown here to activate Id1 gene promoter, repress neurogenesis, and concomitantly induce astrocytogenesis of neuroepithelial cells. As we demonstrate, these two BMPs and their receptors are expressed in neuroepithelial cells. We suggest that BMP2, BMP4 and BMP7 similarly have potential to modulate the fate of neuroepithelial cells from neuronal to astrocytic cells via induction of negative regulatory HLH factors.

Section snippets

Neuroepithelial cell culture

Timed-pregnant ICR mice were sacrificed by cervical dislocation and used to prepare fetal neuroepithelial cells. Neuroepithelial cells were prepared from telencephalons of embryonic day (E) 14.5 mice as previously described (Nakashima et al., 1999a, Nakashima et al., 1999b). Mechanically dissociated cells were plated on 90 mm dish that had been precoated with poly-l-ornithine (Sigma) and fibronectin (Nitta Gelatin Inc), and cultured for 4 days in N2-supplemented DMEM/F12 medium containing 10

Expression of BMPs and their receptors in neuroepithelial cells

In order to study a fate alteration activity of BMP2, BMP4 and BMP7 in neuroepithelial cells, we first examined expression of the three types of BMPs and their cognate type I receptors in these cells. As shown in Fig. 1A, expression of BMP2, BMP4 and BMP7 in the neuroepithelial cells was observed by RT-PCR, which confirmed our previous reports (Nakashima et al., 1999c, Yanagisawa et al., 2001). ALK3 and ALK6 are cognate type I receptors for BMP2 and BMP4, and ALK2 is suggested to be a

Discussion

In our previous studies, we have so far clarified that (1) BMP2 inhibits neurogenesis and concurrently induces astrocytogenesis by altering the fate of neuroepithelial cells from neuronal to astrocytic (Nakashima et al., 2001); (2) BMP2-induced, Smad-dependent up-regulation of negative regulatory HLH factors, Id1, Id3 and Hes5, plays a critical role in the cell fate alteration of neuroepithelial cells (Nakashima et al., 2001); and (3) BMP2 and LIF act in synergy on neuroepithelial cells to

Acknowledgements

We thank Yamanouchi Pharmaceutical for BMP2, Genetics Institute for BMP4, and Dr T. Kuber Sampath (Creative BioMolecules) for BMP7. We are very much grateful to Yuki Noguchi for her excellent secretarial assistance. We also thank Kaori Kaneko for technical help. This work was supported by Grant-in-Aid from Ministry of Education, Culture, Sports, Science and Technology, Human Frontier Science Program, Ichiro Kanehara Foundation, Inamori Foundation, Kato Memorial Bioscience Foundation, Takeda

References (24)

  • T. Ebendal et al.

    Bone morphogenetic proteins and their receptors: potential functions in the brain

    J. Neurosci. Res.

    (1998)
  • Y. Furuta et al.

    Bone morphogenetic proteins (BMPs) as regulators of dorsal forebrain development

    Development

    (1997)
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