Number of adrenergic and islet-1 immunoreactive cells is increased in avian trunk neural crest cultures in the presence of human recombinant osteogenic protein-1.
01 Aug 1995-Developmental Dynamics (Wiley Subscription Services, Inc., A Wiley Company)-Vol. 203, Iss: 4, pp 434-447
TL;DR: The OP‐1‐mediated increase in adrenergic cell number most likely occurs as a result of the enhanced survival of a subpopulation of adrenergic precursors or an increase in their probability of Adrenergic differentiation, but not by increasing the mitotic rate of adren allergic precursor or adrenergic cells themselves.
Abstract: OP-1, also known as BMP-7, is a member of the TGF-β superfamily of proteins and was originally identified on the basis of its ability to induce new bone formation in vivo. OP-1 mRNA is found in the developing kidney and adrenal gland as well as in some brain regions (Ozkaynak et al. [1991] Biochem. Biophys. Res. Commun. 179:116–123). We have tested the effect of recombinant human OP-1 on quail trunk neural crest cultures. The number of catechol-amine-positive cells which developed after 7 days in vitro in the presence of OP-1 was increased in a dose-dependent manner, with a greater than 100-fold maximal stimulation observed. The increase in the number of catecholamine-positive cells in the presence of OP-1 was paralleled by an increase in the number of tyrosine hydroxylase (TH)-positive cells. In contrast, total and melanocyte cell number were unaffected by the presence of OP-1. The number of Islet-1-immunoreactive cells was also increased by OP-1, but to only about half the value seen for TH. Double label experiments revealed these Islet-1-positive cells were a subset of the TH-positive cells. Inhibitors of DNA synthesis prevented the OP-1-mediated increase in adrenergic cell number, indicating that OP-1 does not act on a postmitotic cell population. However, labeling studies with bromodeoxyuridine indicated that OP-1 did not increase the proportion of the cell population engaged in DNA synthesis. Thus, the OP-1-mediated increase in adrenergic cell number most likely occurs as a result of the enhanced survival of a subpopulation of adrenergic precursors or an increase in their probability of adrenergic differentiation, but not by increasing the mitotic rate of adrenergic precursors or adrenergic cells themselves. In contrast to OP-1, TGF-β1 decreased adrenergic cell number. When OP-1 and TGF-β1 were added simultaneously, TGF-β1 antagonized the OP-1-mediated increase in adrenergic cell number in a dose-dependent manner. �1995 Wiley-Liss, Inc.
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TL;DR: It is demonstrated that bone morphogenic protein 2 (BMP2) induces the basic-helix-loop- Helix protein MASH1 and neurogenesis in neural crest stem cells and some smooth muscle differentiation is also observed in BMP2.
847 citations
Cites background or methods from "Number of adrenergic and islet-1 im..."
...Thus, gic properties by neural crest cells (Varley et al., 1995; these growth factors do not play a unitary role in verteReissmann et al., 1995, Soc....
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...seen with rBMP7 used at 100 ng/ml, although in some systems this factor has overlapping effects with BMP2 BMP2 Induces Rapid Neurogenesis in NCSC Clonal Cultures or -4 (Liem et al., 1995; Varley et al., 1995)....
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...No clear effect wasopment of isolated NCSCs in vitro. seen with rBMP7 used at 100 ng/ml, although in some systems this factor has overlapping effects with BMP2BMP2 Induces Rapid Neurogenesis in NCSC Clonal Cultures or -4 (Liem et al., 1995; Varley et al., 1995)....
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TL;DR: Gremlin belongs to a novel gene family that includes the head-inducing factor Cerberus and the tumor suppressor DAN and it is proposed that Gremlin, Cerberus, and DAN control diverse processes in growth and development by selectively antagonizing the activities of different subsets of the TGF beta ligands.
710 citations
TL;DR: Analysis of expression patterns in the central nervous system and heart of the developing mouse embryo suggests that BMP family members can functionally substitute for BMP7 at sites where they colocalize in vivo.
Abstract: BMP7 is expressed at diverse sites in the developing mouse embryo, including visceral endoderm, notochord, heart, eye, kidney, and bone. A null mutation in BMP7 results in defects largely confined to the developing kidney and eye. To examine whether other bone morphogenetic protein (BMP) family members potentially substitute for BMP7 in mutant embryos, thereby restricting the observed defects, we analyzed the expression patterns of BMP2 through BMP7 in wild-type and mutant tissues. In the central nervous system and heart, which develop normally in the absence of BMP7 signaling, expression domains of other BMP family members completely overlap with that of BMP7. The variable expressivity of the eye defect correlates with partially overlapping BMP4 and BMP7 expression domains during early eye induction. The loss of BMP7 signaling in the kidney results in apoptosis in the metanephric mesenchyme, a cell population that exclusively expresses BMP7. Thus, tissue defects observed in BMP7 deficient embryos are restricted to cell populations exclusively expressing BMP7. These data suggest that BMP family members can functionally substitute for BMP7 at sites where they colocalize in vivo.
467 citations
TL;DR: The data demonstrate that isolated mammalian NCSCs uniformly possess SA lineage capacity and further suggest that oxygen levels can influence cell fate and suggests that neural stem cells may exhibit a conserved response to reduced oxygen levels.
Abstract: Isolated neural crest stem cells (NCSCs) differentiate to autonomic neurons in response to bone morphogenetic protein 2 (BMP2) in clonal cultures, but these neurons do not express sympathoadrenal (SA) lineage markers. Whether this reflects a developmental restriction in NCSCs or simply inappropriate culture conditions was not clear. We tested the growth and differentiation potential of NCSCs at ∼5% O_2, which more closely approximates physiological oxygen levels. Eighty-three percent of p75^+P_0 ^− cells isolated from embryonic day 14.5 sciatic nerve behaved as stem cells under these conditions, suggesting that this is a nearly pure population. Furthermore, addition of BMP2 plus forskolin in decreased oxygen cultures elicited differentiation of thousands of cells expressing tyrosine hydroxylase, dopamine-β-hydroxylase, and the SA lineage marker SA-1 in nearly all colonies. Such cells also synthesized and released dopamine and norepinephrine. These data demonstrate that isolated mammalian NCSCs uniformly possess SA lineage capacity and further suggest that oxygen levels can influence cell fate. Parallel results indicating that reduced oxygen levels can also promote the survival, proliferation, and catecholaminergic differentiation of CNS stem cells (Studer et al., 2000) suggests that neural stem cells may exhibit a conserved response to reduced oxygen levels.
424 citations
Cites background from "Number of adrenergic and islet-1 im..."
...Bone morphogenetic proteins (BMPs) have been identified as inducers of SA marker expression in mass cultures of avian and mammalian neural crest cells (Varley et al., 1995; Reissman et al., 1996; Varley and Maxwell, 1996; Lo et al., 1999)....
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TL;DR: Bone morphogenetic proteins act on more lineage-restricted embryonic CNS progenitor cells to promote regional neuronal survival and cellular differentiation and induce selective apoptosis of discrete rhombencephalic neural crest-associated cellular populations.
415 citations
References
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TL;DR: Four areas have seen major progress in the TGF-p superfamily in the last 3 years: structural characterization of the signal ing molecule, isolation of new family members, cloning of receptor molecules, and new genetic tests of the func tions of these factors in different organisms.
Abstract: In the last 10 years, a large family of secreted signaling molecules has been discovered that appear to mediate many key events in normal growth and development. The family is known as the TGF-p superfamily (Massague 1990), a name taken from the first member of the family to be isolated (transforming growth factor-^l). This name is somewhat misleading, because TGF-p 1 has a large number of effects in different systems (Spom and Roberts 1992). It actually inhibits the proliferation of many different cell lines, and its original "transforming" activity may be due to secondary effects on matrix pro duction and synthesis of other growth factors (Moses et al. 1990). The two dozen other members of the TGF-p superfamily have a remarkable range of activities. In Diosophila, a TGF-p-related gene is required for dorsoventral axis formation in early embryos, communication between tissue layers in gut development, and correct proximal distal patterning of adult appendages. In Xenopus, a TGF-p-related gene is expressed specifically at one end of fertilized eggs and may function in early signaling events that lay out the basic body plan. In mammals, TGF-p-related molecules have been found that control sexual development, pituitary hormone production, and the creation of bones and cartilage. The recognition of TGF-p superfamily members in many different organ isms and contexts provides one of the major unifying themes in recent molecular studies of animal growth and development. The rough outlines of the TGF-p family were first rec ognized in the 1980s. Since that time, a number of ex cellent reviews have appeared that summarize the prop erties of different family members (Ying 1989; Massague 1990; Lyons et al. 1991; Spom and Roberts 1992). Here, I will focus on four areas that have seen major progress in the last 3 years: structural characterization of the signal ing molecule, isolation of new family members, cloning of receptor molecules, and new genetic tests of the func tions of these factors in different organisms.
2,092 citations
TL;DR: Results indicate that BMP-2 specifically converts the differentiation pathway of C2C12 myoblasts into that of osteoblast lineage cells, but that the conversion is not heritable.
Abstract: The implantation of bone morphogenetic protein (BMP) into muscular tissues induces ectopic bone formation at the site of implantation. To investigate the mechanism underlying this process, we examined whether recombinant bone morphogenetic protein-2 (BMP-2) converts the differentiation pathway of the clonal myoblastic cell line, C2C12, into that of osteoblast lineage. Incubating the cells with 300 ng/ml of BMP-2 for 6 d almost completely inhibited the formation of the multinucleated myotubes expressing troponin T and myosin heavy chain, and induced the appearance of numerous alkaline phosphatase (ALP)-positive cells. BMP-2 dose dependently induced ALP activity, parathyroid hormone (PTH)-dependent 3',5'-cAMP production, and osteocalcin production at concentrations above 100 ng/ml. The concentration of BMP-2 required to induce these osteoblastic phenotypes was the same as that required to almost completely inhibit myotube formation. Incubating primary muscle cells with 300 ng/ml of BMP-2 for 6 d also inhibited myotube formation, whereas induced ALP activity and osteocalcin production. Incubation with 300 ng/ml of BMP-2 suppressed the expression of mRNA for muscle creatine kinase within 6 h, whereas it induced mRNA expression for ALP, PTH/PTH-related protein (PTHrP) receptors, and osteocalcin within 24-48 h. BMP-2 completely inhibited the expression of myogenin mRNA by day 3. By day 3, BMP-2 also inhibited the expression of MyoD mRNA, but it was transiently stimulated 12 h after exposure to BMP-2. Expression of Id-1 mRNA was greatly stimulated by BMP-2. When C2C12 cells pretreated with BMP-2 for 6 d were transferred to a colony assay system in the absence of BMP-2, more than 84% of the colonies generated became troponin T-positive and ALP activity disappeared. TGF-beta 1 also inhibited myotube formation in C2C12 cells, and suppressed the expression of myogenin and MyoD mRNAs without inducing that of Id-1 mRNA. However, no osteoblastic phenotype was induced by TGF-beta 1 in C2C12 cells. TGF-beta 1 potentiated the inhibitory effect of BMP-2 on myotube formation, whereas TGF-beta 1 reduced ALP activity and osteocalcin production induced by BMP-2 in C2C12 cells. These results indicate that BMP-2 specifically converts the differentiation pathway of C2C12 myoblasts into that of osteoblast lineage cells, but that the conversion is not heritable.
1,410 citations
TL;DR: By analyzing the hearts of quail-chick chimeras, it was found that neural crest cells at the level of occipital somites 1 to 3 migrate to the region of the aorticopulmonary septum, resulting in common arterial outflow channels or transposition of the great vessels.
Abstract: By analyzing the hearts of quail-chick chimeras, it was found that neural crest cells at the level of occipital somites 1 to 3 migrate to the region of the aorticopulmonary septum. Bilateral removal of this neural crest population prior to migration causes malformation of the aorticopulmonary septum resulting in common arterial outflow channels or transposition of the great vessels.
1,054 citations
TL;DR: Results suggest thatALK-3 and ALK-6 are type I receptors for OP-1 and BMP-4; in addition, ALk-2 is a type I receptor shared by activin and OP- 1, but not by B MP-4.
745 citations
TL;DR: Results clearly indicate that rhBMP- 2 is involved, at least in vitro, not only in inducing differentiation of osteoblast precursor cells into more mature osteOBlast-like cells, but also in inhibiting myogenic differentiation.
Abstract: The in vitro effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) on osteogenic and myogenic differentiation was examined in two clonal cell lines of rat osteoblast-like cells at different differentiation stages, ROB-C26 (C26) and ROB-C20 (C20). The C26 is a potential osteoblast precursor cell line that is also capable of differentiating into muscle cells and adipocytes; the C20 is a more differentiated osteoblastic cell line. Proliferation was stimulated by rhBMP-2 in C26 cells, but inhibited in C20 cells. rhBMP-2 greatly increased alkaline phosphate (ALP) activity in C26 cells, but not in C20 cells. The steady-state level of ALP mRNA was also increased by rhBMP-2 in C26 cells, but not in C20 cells. Production of 3',5'-cAMP in response to parathyroid hormone (PTH) was dose-dependently enhanced by adding rhBMP-2 in both C26 and C20 cells, though the stimulatory effect was much greater in the former. There was neither basal expression of osteocalcin mRNA nor its protein synthesis in C26 cells, but they were strikingly induced by rhBMP-2 in the presence of 1 alpha,25-dihydroxyvitamin D3. rhBMP-2 induced no appreciable changes in procollagen mRNA levels of type I and type III in the two cell lines. Differentiation of C26 cells into myotubes was greatly inhibited by adding rhBMP-2. The inhibitory effect of rhBMP-2 on myogenic differentiation was also observed in clonal rat skeletal myoblasts (L6). Like BMP-2, TGF-beta 1 inhibited myogenic differentiation. However, unlike BMP-2, TGF-beta 1 decreased ALP activity in both C26 and C20 cells. TGF-beta 1 induced neither PTH responsiveness nor osteocalcin production in C26 cells, but it increased PTH responsiveness in C20 cells. These results clearly indicate that rhBMP-2 is involved, at least in vitro, not only in inducing differentiation of osteoblast precursor cells into more mature osteoblast-like cells, but also in inhibiting myogenic differentiation.
745 citations