The Bone Morphogenetic Protein Type Ib Receptor Is a Major Mediator of Glial Differentiation and Cell Survival in Adult Hippocampal Progenitor Cell Culture

Abstract

Bone morphogenetic proteins (BMPs) act as growth regulators and inducers of differentiation. They transduce their signal via three different type I receptors, termed activin receptor-like kinase 2 (Alk2), Alk3, or bone morphogenetic protein receptor Ia (BMPRIa) and Alk6 or BMPRIb. Little is known about functional differences between the three type I receptors. Here, we have investigated consequences of constitutively active (ca) and dominant negative (dn) type I receptor overexpression in adultderived hippocampal progenitor cells (AHPs). The dn receptors have a nonfunctional intracellular but functional extracellular domain. They thus trap BMPs that are endogenously produced by AHPs. We found that effects obtained by overexpression of dnAlk2 and dnAlk6 were similar, suggesting similar ligand binding patterns for these receptors. Thus, cell survival was decreased, glial fibrillary acidic protein (GFAP) expression was reduced, whereas the number of oligodendrocytes increased. No effect on neuronal differentiation was seen. Whereas the expression of Alk2 and Alk3 mRNA remained unchanged, the Alk6 mRNA was induced after impaired BMP signaling. After dnAlk3 overexpression, cell survival and astroglial differentiation increased in parallel to augmented Alk6 receptor signaling. We conclude that endogenous BMPs mediate cell survival, astroglial differentiation and the suppression of oligodendrocytic cell fate mainly via the Alk6 receptor in AHP culture. INTRODUCTIONBone morphogenetic proteins (BMPs) are pleiotropic cytokines and constitute the largest subfamily of the transforming growth factor-␤ (TGF-␤) superfamily. Depending on concentration and cell type, they can act as growth regulators as well as inducers of differentiation (Panchision and McKay, 2002). They cause apoptosis in early central nervous system (CNS) precursor cells (Furuta et al., 1997), neuronal differentiation in midgestation 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 these molecules govern such a diverse pattern of action. The distinct profile of ligand and receptor expression in different regions of the brain at a given stage of development suggests actions specific for the BMP factor and receptor. Yet, it has been difficult to characterize signal transduction cascades that mediate distinct actions.The BMP ligands are subdivided into groups, based on structural homologies. Thus, BMP2 and 4 belong to the decapentaplegic (dpp) subgroup; BMP5, 6, and 7 to the 60A subgroup; and GDF5 and 6 to yet another one (Kawabata et al., 1998). All BMPs signal via a tetrameric complex of two out of three type II receptors, namely, BMP receptor II (BMPRII), activin receptor type II (ActRII), and ActRIIB; and two out of three BMP type I receptors, namely, Alk 2, 3, and 6 (reviewed in Balemans and Van Hul, 2002). A given ligand can induce the formation of heteromeric complexes between different receptors and a given receptor can recognize different lig...

Pathogenic Mutation of ALK2 Inhibits Induced Pluripotent Stem Cell Reprogramming and Maintenance: Mechanisms of Reprogramming and Strategy for Drug Identification

“…Whereas ALK3 and ALK6 phosphorylates Smad1, 5, and 8, ALK2 only phosphorylates Smad1 and 5 under physiological conditions [44]. In addition, ALK3 signaling has a functionally different effect from that of ALK2 and 6 on cellular apoptosis of hippocampal progenitors [45]. These studies can support our results that the effect of ALK2 on iPSC generation is different from that of ALK3.…”

BMPR1a Signaling Determines Numbers of Oligodendrocytes and Calbindin-Expressing Interneurons in the Cortex

“…We therefore conclude that BMPR1a mediates suppressive effects of BMPs on oligodendroglial progenitors. However, a previous study has reported that overexpression of dominant-negative (dn) BMPR1b, but not dnBMPR1a, in cultured adult hippocampal progenitors increases immature oligodendroglial numbers (Brederlau et al, 2004). This is in contrast to our findings, possibly reflecting differences between our in vivo data and the in vitro data in that study, differences between developing animals and the adult cells used in that study, or examination in that study of a restricted subset of hippocampal progenitor cells that do not normally generate the major populations of oligodendrocytes in the brain.…”

“…BMPs bind to heteromeric receptors formed by type I (BMPR1a, BMPR1b, Alk2) and type II (BMPRII) subunits (Koenig et al, 1994;ten Dijke et al, 2003). Several studies suggest that BMPR1b mediates the effects of BMPs on exit from cell cycle and terminal differentiation of progenitor cells (Panchision et al, 2001;Gulacsi and Lillien, 2003;Brederlau et al, 2004). However, null mutation of BMPR1b produces no apparent phenotype in the nervous system (Yi et al, 2000), whereas loss of BMPR1a leads to abnormal early forebrain development (Davis et al, 2004) and loss of choroid plexus later in development (Hebert et al, 2002).…”

ADAM-17/Tumor Necrosis Factor-α-Converting Enzyme Inhibits Neurogenesis and Promotes Gliogenesis from Neural Stem Cells

“…As a control, we show the additive effect found when GM6001 was applied together with noggin (Fig. 1J), which decreases gliogenesis by a different mechanism, implying bone morphogenetic protein (BMP) inhibition [12,42,43] Neural Precursors from Postnatal SVZ Expressed Several ADAMs and EGFR Ligands and Released TGF-a Through a Metalloprotease-Mediated Mechanism…”