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First published online September 14, 2006
Stem Cells Vol. 25 No. 1 January 2007, pp. 63 -68
doi:10.1634/stemcells.2006-0339; www.StemCells.com
© 2007 AlphaMed Press

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TISSUE-SPECIFIC STEM CELLS

Concise Review: Bone Morphogenetic Protein Pleiotropism in Neural Stem Cells and Their Derivatives—Alternative Pathways, Convergent Signals

Hui-Ling Chen, David M. Panchision

Center for Neuroscience Research, Children's National Medical Center, Washington, DC, USA

Key Words. Apoptosis • TGF-ß receptor • Proliferation • Pleiotropic effects • Neural stem cell • Neural differentiation • Growth factor Bone morphogenetic protein • Bone morphogenetic protein receptor • Smad proteins • Mammalian target of rapamycin p38 mitogen-activated protein kinase • Neural crest

Correspondence: David M. Panchision, Ph.D., Children's National Medical Center, Center for Neuroscience Research, 111 Michigan Avenue NW, 5th Floor, Suite 5340, Washington, DC 20010, USA. Telephone: 202-884-2269; Fax: 202-884-4988; e-mail: dpanchision{at}cnmcresearch.org

Received June 2, 2006; accepted for publication September 7, 2006.
First published online in STEM CELLS EXPRESS   September 14, 2006.


   ABSTRACT
Top
 Abstract
Introduction
 Mechanisms Underlying BMP...
 Conclusion
 Disclosures
 Acknowledgments
 References
 
Bone morphogenetic proteins (BMPs) are a class of morphogens that are critical regulators of the central nervous system (CNS), peripheral nervous system, and craniofacial development. Modulation of BMP signaling also appears to be an important component of the postnatal stem cell niche. However, describing a comprehensive model of BMP actions is complicated by their paradoxical effects in precursor cells, which include dorsal specification, promoting proliferation or mitotic arrest, cell survival or death, and neuronal or glial fate. In addition, in postmitotic neurons BMPs can promote dendritic growth, act as axonal chemorepellants, and stabilize synapses. Although many of these responses depend on interactions with other incoming signals, some reflect the recruitment of distinct BMP signal transduction pathways. In this review, we classify the diverse effects of BMPs on neural cells, focus on the known mechanisms that specify distinct responses, and discuss the remaining challenges in identifying the cellular basis of BMP pleiotropism. Addressing these issues may have importance for stem cell mobilization, differentiation, and cell integration/survival in reparative therapies.


   INTRODUCTION
Top
 Abstract
 Introduction
Mechanisms Underlying BMP...
 Conclusion
 Disclosures
 Acknowledgments
 References
 
In mammalian nervous system development, precursor cells are subdivided into regionally specific groups, expanded in numbers and then differentiated into distinct neurons and glia. The nervous system originates as an epithelium composed of rapidly proliferating precursors that maintain connections to both the ventricular and pial surface. The epithelium undergoes morphogenic movements to transform from a neural plate to a neural tube [1, 2]. As precursor cells undergo mitotic arrest, they delaminate from the ventricular surface and form a mantle layer that becomes larger and more complex as gestation proceeds [3]. Soon after birth, the proliferative zone has become a proportionally minuscule region of the nervous system, while the last neurons, astrocytes, and oligodendrocytes are migrating to their correct positions to form functional networks. However, this proliferative zone continues to generate new neurons into adulthood, the best-documented areas being the hippocampal dentate gyrus and the rostral migratory stream [4]. Many of these events are influenced by the important class of morphogens called bone morphogenetic proteins (BMPs). In this review, we briefly classify the diverse effects of BMPs on neural precursors and their derivatives. We focus primarily on what is known about the mechanisms that mediate these pleiotropic responses. Finally, we comment on the clinical implications and the challenges that remain in developing a comprehensive cellular model of BMP actions in the nervous system.


   MECHANISMS UNDERLYING BMP PLEIOTROPIC ACTIONS
Top
 Abstract
 Introduction
 Mechanisms Underlying BMP...
Conclusion
 Disclosures
 Acknowledgments
 References
 
Categorization of BMP Responses in Precursors
BMPs are members of the diverse transforming growth factor ß (TGFß) family of secreted ligands [5]. They were originally identified by their bone-forming actions and also play important but paradoxical roles in nervous system development (Fig. 1). BMPs are expressed at high levels at the lateral edges of the neural plate and subsequently in the dorsal midline of the neural tube [6, 7]. A BMP activity gradient induces dorsal identity markers indicative of neural crest or dorsal interneuron precursors [8–11], as well as choroid plexus epithelium [12, 13], cortical hem, and dorsal cortex [14] in the forebrain. Application of the same BMPs has been shown to paradoxically stimulate both proliferation [12, 15, 16] and mitotic arrest [12, 17, 18]. BMPs also have important effects on terminal fates. Precursor cells cultured in vitro exhibit age-dependent biases in terminal fate choice that mirror the in vivo developmental progression of cell type differentiation. Neural precursor cells isolated from progressively older embryos respond to BMPs first with apoptosis [6, 19], then with neuronal differentiation in mid-gestation [17, 20], and finally with glial differentiation in late gestation and into adulthood [21, 22]. In the adult brain, the extracellular BMP inhibitor Noggin is expressed by ependymal cells in the lateral ventricle and can redirect multipotent type B glial cells to a neuronal fate [23]; this implicates BMPs as niche signals and their repression as a means of stem cell mobilization. One way of categorizing BMP responses in precursors is those that are inductive (e.g., dorsal specification, proliferation) and those that are terminating (e.g., apoptosis, mitotic arrest, neuronal differentiation) [12]. It is unclear how BMPs cause such a wide variety of responses, but it may be due to (a) the activation of different BMP signal transduction pathways and/or (b) other signals that modulate the response to BMPs. Below, we describe evidence for both of these methods of control.


Figure 1
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  		Figure 1. BMPs promote dorsal identity, regulate proliferation, and promote multiple terminal fates. BMPs are expressed at the dorsal midline and promote dorsal fates based on intensity of activation. SHH acts antagonistically from the ventral midline to promote ventral fates. BMPs can promote or inhibit neural precursor proliferation, depending on the assay. The ultimate fate of the cells correlates with the time at which precursors undergo mitotic arrest. The expansion phase is devoted to increasing precursor number. Apoptosis is a prominent part of this phase, especially at the dorsal midline. The neurogenic phase is devoted to the generation of neurons. The gliogenic phase is devoted to glial differentiation. Different precursor domains pass through each phase at different times. Abbreviations: BMP, bone morphogenetic protein; SHH, sonic hedgehog.

 
Redundancy and Specificity in BMP Signal Transduction
There are a large number of BMP signal transduction components. Approximately 30 members of the BMP/growth and differentiation factor subfamily of TGFß ligands have been identified. Some BMP-related ligands are known to be involved in the generation of specific cell types [24, 25], but there is evidence that many act in a redundant manner [26–28]. BMPs exert their effects by activating a tetramer complex of type I and type II receptors (Fig. 2). The type II receptor is primarily a ligand binding component; both BMP receptor II (BMPRII) and Activin receptor IIB (ActRIIB) are functional type II receptors for BMPs. Type I receptors also have BMP-binding properties and are responsible for transducing the signal into the cell; BMPRIA (Alk3), BMPRIB (Alk6), and ActRI (Alk2) are all known to transduce BMP signals [29]. Transgenic mice expressing activated mutants of BMPRIA and BMPRIB under the control of the Nestin promoter generate distinct effects; BMPRIA activation induces dorsal identities and maintains the precursor state, whereas BMPRIB promotes apoptosis and terminal differentiation [12]. These results were qualitatively different regardless of copy number: activated BMPRIA caused holoprosencephaly due to specification of the entire forebrain to choroid plexus epithelium, whereas activated BMPRIB caused exencephaly due to increased apoptosis. Cells that initially express only Bmpr1a will induce expression of Bmpr1b within an hour of exposure to BMPs, suggesting a sequential mechanism of BMPRIA-mediated induction followed by BMPRIB-mediated termination [12]. This is supported by dominant negative blocking studies showing that Bmpr1b is required for neuronal terminal differentiation in vitro [12, 30]. Conversely, other studies have shown equivalent responses to these activated mutants and have used them interchangeably to characterize mechanisms of dorsal patterning in chick spinal cord [31, 32]. The conflicting results may be due to the nature of overexpression studies, which are subject to variability in cDNA animal species, promoter strength/selectivity, and method of gene delivery (transgenic, viral infection, or electroporation).


Figure 2
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  		Figure 2. BMP signaling in the cell. Multiple BMPs activate the BMPRIA (Alk3), BMPRIB (Alk6), and ActRI (Alk2) with differing affinities; this binding can be blocked by endogenous antagonists such as Noggin, Chordin, and Cerberus. Activated BMPRs activate the canonical SMAD pathway; BMPs can also activate mitogen-activated protein kinases, the kinase mTOR/FRAP, and LIM kinase 1. Activated SMADs translocate to the nucleus, complex with coactivators (e.g., CBP/p300) or corepressors, and regulate transcription of target genes that promote dorsal identities, proliferation, mitotic arrest, terminal differentiation, or apoptosis. SMAD function is modulated by interaction with other nuclear factors such as STAT proteins (activated by LIF, CNTF, or BMPs themselves) to promote a glial identity, or with Neurogenin-1, which prevents STAT complexing with CBP/p300 and promotes a neuronal identity. Abbreviations: BMP, bone morphogenetic protein; BMPR, bone morphogenetic protein receptor; CBP, CREB binding protein; CNTF, ciliary neurotrophic factor; ERK, extracellular signal-related kinase; LIF, leukemia inhibitory factor; LIMK1, LIM kinase 1; mTOR, mammalian target of rapamycin; SMAD, small/male tail abnormal/mothers against decapentaplegic homolog; STAT, signal transducer and activator of transcription.

 
More recent targeted null mutants have indicated that substantial functional redundancy exists when both receptors are expressed. Conventional Bmpr1a–/– mice die before gastrulation [33] and are not useful for studying central nervous system (CNS) development. A Bmpr1a conditional null under the control of the Foxg1 (Bf1) promoter showed a failure of choroid plexus generation, where Bmpr1b expression was absent, but no other obvious phenotype in the forebrain [13]. An absence of phenotype in a conditional null raises the possibility that BMPRIA may exert actions on the presumptive cortex prior to the onset of Foxg1-Cre expression. Furthermore, Foxg1 expression (required for Cre/lox recombination) itself indicates that cortical induction and expansion has already begun [34] and is likely to already be under the control of signals other than BMPs, such as Wnt and fibroblast growth factor (FGF) ligands [35–37]. Indeed, there is evidence for a positive role of BMPs in promoting cortical precursor identity [35, 38], but it is likely to be before Foxg1 induction, since Foxg1 and BMP signaling are then mutually repressive [34, 39].

Two Bmpr1b-null mice have been generated, one of which knocks out the gene globally [40]. This mutant displayed disrupted differentiation in the distal limb and defective reproductive function, but no obvious defect in the CNS [40, 41]. A double knockout involving a Brn3a-Cre conditional (beginning at E8.5) ablation of Bmpr1a crossed with a Bmpr1b–/– mouse led to spinal cord pattern and differentiation defects not seen with either null individually [42]. Similar results were found for cerebellar granule cells [43]. Many of the spinal defects appear to involve later stages of neurogenic precursor maintenance, such as the loss of a pre-existing roof plate and DI1/DI2 dorsal precursor identity. Wnt expression, a downstream target of BMPs, is somewhat diminished but not ablated, suggesting that very early responses involved in initial patterning have still occurred. However, these double-null studies indicate that there is substantial receptor redundancy in the maintenance of dorsal cell identity. It is likely that initial specification occurs through BMPRIA, since Bmpr1b expression does not begin until approximately E9.0 [12, 44].

The activated type I receptors in turn phosphorylate the canonical 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 (Fig. 2) [45]. There is no evidence to date that differential activation of Smad1, Smad5, or Smad8 protein can account for the distinct actions of BMPs. However, noncanonical signaling pathways have been implicated as responding to BMP stimulation. BMP treatment of CNS precursor cells at high density leads to the activation of both small/male tail abnormal/mothers against decapentaplegic homologs (SMADs) and a multifunctional serine-threonine kinase called mammalian target of rapamycin/FKBP12-rapamycin-associated protein (mTOR/FRAP). mTOR/FRAP then binds to and serine-phosphorylates Stat3, which selectively promotes the generation of glia [46]. However, Stat3 does not bind its cognate DNA sequence at low cell density, suggesting that an additional density-dependent signal promotes responsiveness of the mTOR/signal transducer and activator of transcription (STAT) pathway. Apoptosis is promoted in both fetal cortical precursors and P19 teratocarcinoma cells by another noncanonical pathway involving the p38 mitogen-activated protein kinase (p38MAPK) [47]. Evidence from mesenchymal cells indicates that the manner of receptor oligomerization may influence the activation of distinct p38MAPK and Smad pathways [48–50]. BMP stimulation of pre-existing complexes leads to p38MAPK activation, whereas recruitment of complexes leads to SMAD activation [49]. One intriguing possibility, which could explain the discrepancies between the activated and null mutant data, is that expression of constitutively active (c.a.) Bmpr1a versus c.a. Bmpr1b may differentially alter the clustering dynamics of the receptor complexes, thus leading to the activation of distinct intracellular signals and thus either induction or termination responses.

BMP responses are ultimately mediated through the transcriptional activation of target genes. Wnt1, which is induced by BMPRIA activation [12], also acts as a mitogen [51]. Inhibition of BMPs by Noggin decreases Wnt1/3a expression in the roof plate and decreases proliferation; specifically blocking Wnt activity leads to a similar decrease in proliferation without replicating the Noggin-induced patterning defects [52]. This indicates that Wnt signaling is at least partly responsible for the expansion of BMP-dorsalized precursors [12]. BMP-responsive transcription factors such as Zic1 are also known to repress terminal differentiation through the repression of neurogenic basic helix-loop-helix (bHLH) genes [53]. Recently, it was shown that BMPs promote pluripotency of embryonic stem cells by inducing the expression of the bHLH gene Id1 [54] while inhibiting p38MAPK activation [55]. Since BMPs are capable of inducing Id genes and activating/inhibiting p38MAPK, it remains to be seen how these alternative mechanisms might control the balance of proliferation, lineage determination, and differentiation in neural precursors.

Convergence of BMP and Other Signals
Although BMP ligands are expressed at the lateral edge/dorsal-midline throughout development [6], the generation of distinct subsets of dorsal precursors occurs within defined temporal windows. Neural crest delaminates from the neural/non-neural border at the time of neural tube closure [56]. One important player is Sox9, which is required for BMPs to induce Snail2, a zinc-finger protein that promotes an epithelial-mesenchymal transition (EMT) in chick. Sox9 activity is enhanced by protein kinase A (PKA), indicating that convergent activity between BMP and PKA activators promote neural crest emigration from the neural tube [57]. Upon neural tube closure, early BMP activation can induce roof plate, whereas equivalent activation in later gestation induces the dorsal interneuron domain. The differential activation of the transcription factors Msx1 and Msx3 [32] plays a role in this switch in fates. A recent study showed a cooperative interaction between FGF2 and BMPs in the CNS to neural crest transition. BMP2 (or BMP4, BMP7) induces cortical stem cells to fates characteristic of either neural crest or choroid plexus mesenchyme (CPm), an anterior cell type of undetermined origin. This neural crest/CPm induction occurs both in dissociated cell culture and E14.5 cortical explants, but only when cells have been simultaneously activated by FGF2. Neither epidermal growth factor (EGF) nor insulin-like growth factor can substitute for FGF2, suggesting that FGF2 is required, independent of its mitogenic actions. The initial response involves the induction of Msx1, a marker of dorsal midline, Snail1, a marker of EMT in rodents, and p75NGFR, which marks certain dorsal precursors/derivatives including neural crest. Activation of ß-catenin, a mediator of Wnt activity, occurs within 24 hours, followed by EMT over the course of 1–4 days [58].

This suggests that either FGF2 may become more limiting as gestation proceeds or that EGF expands or instructs a distinct precursor that is insensitive to the dorsalizing actions of BMPs. In vitro studies indicate that dissociated cells from early gestation CNS tissue are responsive to FGF2 but not EGF, but that EGF responsiveness is promoted by FGF2 expansion or in later gestational ages, leading to precursors that are responsive to both mitogens [59]. EGF expansion of multipotent precursors promotes gliogenic competence [60], but BMP treatment of midgestation cortical explants prevents EGF responsiveness [61]. Conversely, BMP treatment of isolated fetal cerebellar precursors [62] or polysialated neural cell-adhesion molecule+ progenitors [63] leads to rapid neuronal differentiation. Late-gestation subventricular zone (SVZ) precursor cotreatment with EGF/leukemia inhibitory factor (LIF) yielded stellate glia that remained capable of proliferation (suggesting a radial glia fate), whereas EGF/BMP treatment generated flattened postmitotic glia [64]. These findings support the idea that BMPs can have separate, and perhaps antagonistic, sets of actions on early versus late neural precursors.

A number of intracellular mechanisms have been implicated in the determination of neuron versus glial fates. One study shows that glial differentiation in response to BMPs requires the coactivators CREB binding protein (CBP)/p300 in a complex with STAT and SMAD proteins [65]. Another study indicated that SMAD action is not required for gliogenesis but is promoted by BMPs acting through mTOR/FRAP and STAT [46] in conjunction with a density or contact-dependent signal [46, 66]. Although STAT3 activity is a critical glial differentiation signal [67], increased STAT tyrosine phosphorylation in late gestation is not by itself sufficient for gliogenesis [60]. Since BMP-activated mTOR/FRAP causes serine phosphorylation of STAT [46], this suggests that convergent activation of STAT by LIF and BMPs is involved in glial differentiation.

The differentiation of glia by either BMPs or ciliary neurotrophic factor (CNTF) is inhibited by the basic helix-loop-helix protein Neurogenin1, which acts in part by sequestering the CBP/SMAD1 complex from association with STAT proteins. In CNS precursor cells expressing high levels of Neurogenin1, BMPs induce neuronal rather than glial differentiation [68]. Likewise, the generation of oligodendrocytes is inhibited by BMPs [69] via induction of the Id class of bHLH proteins [70]; Id2 and -4 (but not -1 or -3) act as dominant negative binding partners for the oligodendrocyte determination factors Olig1/2. Previous studies have shown that the same signaling molecules can promote either precursor cell self-renewal or gliogenesis. Notch activation is required for the maintenance of early gestation neural precursor cells [71] but also promotes gliogenesis in precursor cells from older embryos [72, 73], particularly in response to BMP treatment [74]. Likewise, mTOR/FRAP is a critical regulator of cell growth and proliferation in many cell types [75], although it promotes gliogenesis in neural precursor cells [46]. Thus, self-renewal and gliogenesis share molecular mechanisms that generally antagonize the actions of neurogenic molecules and bias the response of precursor cells to BMPs. However, there is still no clear explanation for how this transition from self-renewal signal to gliogenic signal occurs.

BMP Effects on Postmitotic Cells
The pleiotropic effects of BMPs in postmitotic cells are also being increasingly recognized. In the postnatal SVZ, BMPs promote survival of neuronal-committed type A cells, which express both BMPRIA and BMPRIB, whereas they have no survival effect on BMPRIA+ BMPRIB– type B/C cells. This suggests that BMPRIB specifically mediates survival effects when induced in postmitotic neurons or their immediate progenitors. BMPs regulate axon pathfinding and dendritic arborization in both CNS [76] and peripheral nervous system (PNS) [77] neurons. Roof-plate-derived BMPs act as chemorepellants of commissural axons by orienting their growth cones in a ventral direction during spinal cord development [78, 79]. Antagonizing BMP signaling with Noggin resulted in abnormal growth of retinal ganglion axons and failed optic nerve head development in chick retina [80] and influence cell survival [81]. The retinal defect described in BMP blocking experiments was also caused in the Bmpr1b–/– mutant [82]. Because BMPRIA is not expressed in this region, it cannot be argued this is a receptor-specific effect. Work in Drosophila has provided the most detailed description of how BMP signaling coordinates axon and synaptic development. At points where axons reach their targets, target-derived retrograde BMP signaling is required to strengthen the neuromuscular junction [83]. In this case, parallel activation of Wishful Thinking (ortholog of BMPRII) and LIM kinase1 is required for maximal stabilization [84]. Target-mediated specification of Tv neuroendocrine neurons also requires Wishful Thinking, which then activates the downstream targets apterous and squeeze [85]. When these components are misexpressed in other cells, they become ectopic Tv neurons. Thus, this BMP receptor activates a neuron subtype preprogram. It is not known whether BMP signaling through other components would activate this program equally.

Several BMPs also stimulate dendritic growth in neurons from cortical [86], hippocampal [87], striatal [88], and midbrain dopaminergic neurons [89], as well as PNS superior cervical ganglion [77]. Significantly, BMP7 induced dendritic sprouting equivalent to that seen in vivo, without changing axonal growth or survival, suggesting that BMPs may be sufficient and specific for dendritic growth in postmitotic neurons [90, 91]. The actions of BMPs could be antagonized by addition of addition of LIF/CNTF [92] or retinoic acid [93], indicating that the degree of dendritic arborization reflects a balance of multiple inputs. Introduction of dominant negative BMPRIA significantly attenuated Smad1 activation and BMP-induced dendrite growth in rat sympathetic neurons [94]. In a mechanism similar to that seen in Drosophila, treatment of mouse cortical neurons with BMP7 leads to a physical interaction of BMPRII and LIM kinase1 via GTPase activity, which promotes arborization in a SMAD-independent manner [95]. This provides further evidence that BMP signaling components can be recruited in novel configurations to activate other signaling pathways depending on the cell type.

Although numerous studies have shown that BMPs inhibit the generation of oligodendrocytes from precursors, recent evidence suggests that BMPs promote the late stages of oligodendrocyte maturation. Consistent with its earlier negative effect, BMP treatment of immature GalC+ oligodendrocytes inhibited maturation by measurement of key myelin proteins [96]. In another assay, BMPs promoted process formation and remyelinating potential of oligodendrocytes [97], although many of these cells were phenotypically similar to Schwann cells, a neural crest derivative known to be induced by BMPs [58, 74]. Furthermore, this effect of BMPs is likely indirect, since blockade of PDGF signaling prevented the maturation effect of BMPs [98]. However, a late-stage role for BMPs would be consistent with the migration of immature oligodendrocytes into cortical areas close to dorsal midline BMP sources.


   CONCLUSION
Top
 Abstract
 Introduction
 Mechanisms Underlying BMP...
 Conclusion
Disclosures
 Acknowledgments
 References
 
The body of literature to date indicates far more examples of BMP responses being conferred in a context-dependent manner than due to recruitment of alternative signaling pathways. Although the ligands, receptors, and Smad proteins may have substantial redundancy, the elucidation of their function is complicated by their multimeric structure. There is evidence that the stoichiometry of receptor components and mode of recruitment may specify different responses. This may involve preferential activation of p38MAPK, mTOR, or LIM kinase 1 in addition to the canonical SMAD proteins. The story is far from complete. First, a search for alternative pathways has not been performed using proteomic analysis after BMP activation. Second, much of the uncertainty regarding context-dependent signaling is due to the absence of robust prospective identification and characterization of distinct intermediate precursor types. Better methods of functional characterization need to be applied to determine whether BMP stimulation is affecting a stem cell or a restricted progenitor. The lineal relationship between early (EGF-insensitive) and late (EGF-responsive) gestation precursors is still poorly understood and is potentially important to understanding how BMP responses change over time.

The ability to generate a comprehensive model of BMP signaling has important clinical consequences. BMP administration was shown to reduce the infarct area and clinical symptoms in an animal model of stroke [99]. In another study, BMP type I receptors were upregulated in striatum, the terminal target of the substantia nigra dopaminergic neuron, after 6-hydroxydopamine lesioning in a Parkinson disease model [100]. Although the cellular events underlying these responses are not known, they suggest that BMP signaling is an important component of the response to brain injury. The role of BMPs in regulating neuron axon guidance and oligodendrocyte maturation suggests a means of promoting remyelination in traumatic injury. Many candidate cell types for replacement therapies are either promoted (e.g., neural crest) or inhibited (e.g., oligodendrocytes) by BMP signaling. The ability to generate these cells with high efficiency may require exposing precursors to a precise concentration of BMPs or their inhibitors, alone or in combination with other factors. Alternatively, it may require selecting the correct type of committed progenitor from a heterogeneous culture prior to BMP treatment. Although much work remains to be done to elucidate the mechanisms for these BMP responses, the potential is high for translating these results into the treatment of human disorders.


   DISCLOSURES
Top
 Abstract
 Introduction
 Mechanisms Underlying BMP...
 Conclusion
 Disclosures
Acknowledgments
 References
 
The authors indicate no potential conflicts of interest.


   ACKNOWLEDGMENTS
Top
 Abstract
 Introduction
 Mechanisms Underlying BMP...
 Conclusion
 Disclosures
 Acknowledgments
References
 
D.M.P. and H.-L.C. are supported in part by Grant P30HD40677 from the NIH Mental Retardation and Developmental Disabilites Research Center. H.-L.C. is supported by a Haseltine Fellowship.


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 Mechanisms Underlying BMP...
 Conclusion
 Disclosures
 Acknowledgments
 References
 

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