Wnt/BMP signal integration regulates the balance between proliferation and differentiation of neuroepithelial cells in the dorsal spinal cord

Multiple signaling pathways regulate proliferation and differentiation of neural progenitor cells during early development of the central nervous system (CNS). In the spinal cord, dorsal signaling by bone morphogenic protein (BMP) acts primarily as a patterning signal, while canonical Wnt signaling promotes cell cycle progression in stem and progenitor cells. However, overexpression of Wnt factors or, as shown here, stabilization of the Wnt signaling component beta-catenin has a more prominent effect in the ventral than in the dorsal spinal cord, revealing local differences in signal interpretation. Intriguingly, Wnt signaling is associated with BMP signal activation in the dorsal spinal cord. This points to a spatially restricted interaction between these pathways. Indeed, BMP counteracts proliferation promoted by Wnt in spinal cord neuroepithelial cells. Conversely, Wnt antagonizes BMP-dependent neuronal differentiation. Thus, a mutually inhibitory crosstalk between Wnt and BMP signaling controls the balance between proliferation and differentiation. A model emerges in which dorsal Wnt/BMP signal integration links growth and patterning, thereby maintaining undifferentiated and slow-cycling neural progenitors that form the dorsal confines of the developing spinal cord.     

Molecular pathways needed for regeneration of spinal cord and muscle in a vertebrate

The tail of the frog tadpole, comprising spinal cord, muscle, and notochord, regenerates following partial amputation. We show that, in Xenopus, this occurs throughout development, except for a "refractory period" between stages 45 and 47, when tails heal over without regeneration. Regeneration can be enabled during this refractory period by activation of either the BMP or Notch signaling pathways. Conversely, regeneration can be prevented during the later, regenerative, stages by inhibition of either pathway. BMP signaling will cause regeneration of all tissues, whereas Notch signaling activates regeneration of spinal cord and notochord, but not muscle. An activated form of Msx1 can promote regeneration in the same way as BMP signaling. Epistasis experiments suggest that BMP signaling is upstream of Notch signaling but exerts an independent effect on muscle regeneration. The results demonstrate that regenerative capability can be enabled by genetic modifications that reactivate specific components of the developmental program.     

The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation

The bone morphogenetic proteins (BMPs) are a group of powerful morphogens that are critical for development of the nervous system. The effects of BMP signaling on neural stem cells are myriad and dynamic, changing with each stage of development. During early development inhibition of BMP signaling differentiates neuroectoderm from ectoderm, and BMP signaling helps to specify neural crest. Thus modulation of BMP signaling underlies formation of both the central and peripheral nervous systems. BMPs secreted from dorsal structures then form a gradient which helps pattern the dorsal-ventral axis of the developing spinal cord and brain. During forebrain development BMPs sequentially induce neurogenesis and then astrogliogenesis and participate in neurite outgrowth from immature neurons. BMP signaling also plays a critical role in maintaining adult neural stem cell niches in the subventricular zone (SVZ) and subgranular zone (SGZ). BMPs are able to exert such diverse effects through closely regulated temporospatial expression and interaction with other signaling pathways.     

Defining early hematopoietic-fated primitive streak specification of human pluripotent stem cells by the orchestrated balance of Wnt,activin, and BMP signaling

Distinct regions of the primitive streak (PS) have diverse potential to differentiate into several tissues, including the hematopoietic lineage originated from the posterior region of PS. Although various signaling pathways have been identified to promote the development of PS and its mesoderm derivatives, there is a large gap in our understanding of signaling pathways that regulate the hematopoietic fate of PS. Here, we defined the roles of Wnt, activin, and bone morphogenetic protein (BMP) signaling pathways in generating hematopoietic-fated PS from human pluripotent stem cells (hPSCs). We found that the synergistic balance of these signaling pathways was crucial for controlling the PS fate determination towards hematopoietic lineage via mesodermal progenitors. Although the induction of PS depends largely on the Wnt and activin signaling, the PS generated without BMP4 lacks the hematopoietic potential, indicating that the BMP signaling is necessary for the PS to acquire hematopoietic property. Appropriate levels of Wnt signaling is crucial for the development of PS and its specification to the hematopoietic lineage. Although the development of PS is less sensitive to activin or BMP signaling, the fate of PS to mesoderm progenitors and subsequent hematopoietic lineage is determined by appropriate levels of activin or BMP signaling. Collectively, our study demonstrates that Wnt, activin, and BMP signaling pathways play cooperative and distinct roles in regulating the fate determination of PS for hematopoietic development. Our understanding of the regulatory networks of hematopoietic-fated PS would provide important insights into early hematopoietic patterning and possible guidance for generating functional hematopoietic cells from hPSCs in vitro.     

NRAGE mediates p38 activation and neural progenitor apoptosis via the bone morphogenetic protein signaling cascade

Understanding the molecular events that govern neural progenitor lineage commitment, mitotic arrest, and differentiation into functional progeny are germane to our understanding of neocortical development. Members of the family of bone morphogenetic proteins (BMPs) play pivotal roles in regulating neural differentiation and apoptosis during neurogenesis through combined actions involving Smad and TAK1 activation. We demonstrate that BMP signaling is required for the induction of apoptosis of neural progenitors and that NRAGE is a mandatory component of the signaling cascade. NRAGE possesses the ability to bind and function with the TAK1-TAB1-XIAP complex facilitating the activation of p38. Disruption of NRAGE or any other member of the noncanonical signaling cascaded is sufficient to block p38 activation and thus the proapoptotic signals generated through BMP exposure. The function of NRAGE is independent of Smad signaling, but the introduction of a dominant-negative Smad5 also rescues neural progenitor apoptosis, suggesting that both canonical and noncanonical pathways can converge and regulate BMP-mediated apoptosis. Collectively, these results establish NRAGE as an integral component in BMP signaling and clarify its role during neural progenitor development.     

Inhibitory Smads differentially regulate cell fate specification and axon dynamics in the dorsal spinal cord

The roof plate resident BMPs have sequential functions in the developing spinal cord, establishing cell fate and orienting axonal trajectories. These activities are, however, restricted to the dI1–dI3 neurons in the most dorsal region of the spinal cord. What limits the extent of the action of the BMPs to these neurons? To address this question, we have examined both the distribution of the inhibitory Smads (I-Smads), Smad6 and Smad7 in the spinal cord and the consequence of ectopically expressing the I-Smads in chicken embryos. Our studies suggest that the I-Smads function in vivo to restrict the action of BMP signaling in the dorsal spinal cord. Moreover, the I-Smads have distinct roles in regulating the diverse activities of the BMPs. Thus, the ectopic expression of Smad7 suppresses the dI1 and dI3 neural fates and concomitantly increases the number of dI4–dI6 spinal neurons. In contrast, Smad6 most potently functions to block dI1 axon outgrowth. Taken together, these experiments suggest that the I-Smads have distinct roles in spatially limiting the response of cells to BMP signaling.     

The homeobox gene bozozok promotes anterior neuroectoderm formation in zebrafish through negative regulation of BMP2/4 and Wnt pathways

The neuroectoderm of the vertebrate gastrula was proposed by Nieuwkoop to be regionalized into forebrain, midbrain, hindbrain and spinal cord by a two-step process. In the activation step, the Spemann gastrula organizer induces neuroectoderm with anterior character, followed by posteriorization by a transforming signal. Recently, simultaneous inhibition of BMP and Wnt signaling was shown to induce head formation in frog embryos. However, how the inhibition of BMP and Wnt signaling pathways specify a properly patterned head, and how they are regulated in vivo, is not understood. Here we demonstrate that the loss of anterior neural fates observed in zebrafish bozozok (boz) mutants occurs during gastrulation due to a reduction and subsequent posteriorization of neuroectoderm. The neural induction defect was correlated with decreased chordino expression and consequent increases in bmp2b/4 expression, and was suppressed by overexpression of BMP antagonists. Whereas expression of anterior neural markers was restored by ectopic BMP inhibition in early boz gastrulae, it was not maintained during later gastrulation. The posteriorization of neuroectoderm in boz was correlated with ectopic dorsal wnt8 expression. Overexpression of a Wnt antagonist rescued formation of the organizer and anterior neural fates in boz mutants. We propose that boz specifies formation of anterior neuroectoderm by regulating BMP and Wnt pathways in a fashion consistent with Nieuwkoop's two-step neural patterning model. boz promotes neural induction by positively regulating organizer-derived chordino and limiting the antineuralizing activity of BMP2b/4 morphogens. In addition, by negative regulation of Wnt signaling, boz promotes organizer formation and limits posteriorization of neuroectoderm in the late gastrula.     

Signal transduction of bone morphogenetic protein receptors

Bone morphogenetic proteins (BMPs) play a crucial role during all stages of embryonic development. Although only two major signaling pathways have been characterized (the p38 and Smad pathways), the BMP signaling is complex and includes several negative feedback mechanisms. This article reviews the current state of BMP receptor signaling and provides a summary of the crosstalk of the BMP receptor pathway with other major signaling pathways.     

Canonical Wnt signalling requires the BMP pathway to inhibit oligodendrocyte maturation

OLs (oligodendrocytes) are the myelinating cells of the CNS (central nervous system), wrapping axons in conductive sheathes to ensure effective transmission of neural signals. The regulation of OL development, from precursor to mature myelinating cell, is controlled by a variety of inhibitory and inductive signalling factors. The dorsal spinal cord contains signals that inhibit OL development, possibly to prevent premature and ectopic precursor differentiation. The Wnt and BMP (bone morphogenic protein) signalling pathways have been identified as dorsal spinal cord signals with overlapping temporal activity, and both have similar inhibitory effects on OL differentiation. Both these pathways feature prominently in many developmental processes and demyelinating events after injury, and they are known to interact in complex inductive, inhibitive and synergistic manners in many developing systems. The interaction between BMP and Wnt signalling in OL development, however, has not been extensively explored. In the present study, we examine the relationship between the canonical Wnt and BMP pathways. We use pharmacological and genetic paradigms to show that both Wnt3a and BMP4 will inhibit OL differentiation in vitro. We also show that when the canonical BMP signalling pathway is blocked, neither Wnt3a nor BMP4 have inhibitory effects on OL differentiation. In contrast, abrogating the Wnt signalling pathway does not alter the actions of BMP4 treatment. Our results indicate that the BMP signalling pathway is necessary for the canonical Wnt signalling pathway to exert its effects on OL development, but not vice versa, suggesting that Wnt signals upstream of BMP.     

自噬通过BDNF/TrkB信号通路对脊髓损伤的保护作用

脊髓型颈椎病(cervical spondylotic myelopathy, CSM)是临床常见病、多发病,由该病引起的脊髓受损而产生的脊髓功能障碍是其最常见的临床特征。在脊髓损伤中,多种因素能通过自噬相关信号通路而激活自噬,适度的自噬可以对脊髓损伤起到神经保护作用,而增加细胞存活率、恢复和增加自噬通量可以改善损伤后的脊髓功能的恢复;在CSM脊髓损伤中,脑源性神经营养因子(brain derived neurotrophic factor, BDNF)与其受体原肌球蛋白受体激酶B(tropomyosin receptor kinase B, TrkB)及其相关通路是参与保护神经细胞的重要途径之一,细胞自噬在这一过程中起到了重要的调节作用。本文通过阐释自噬与BDNF/TrkB信号通路在CSM过程中的作用及其对脊髓损伤的保护机制,以期对基础研究及临床研究提供理论支持。     

Electrical activity as a developmental regulator in the formation of spinal cord circuits

Spinal cord development is a complex process involving generation of the appropriate number of cells, acquisition of distinctive phenotypes and establishment of functional connections that enable execution of critical functions such as sensation and locomotion. Here we review the basic cellular events occurring during spinal cord development, highlighting studies that demonstrate the roles of electrical activity in this process. We conclude that the participation of different forms of electrical activity is evident from the beginning of spinal cord development and intermingles with other developmental cues and programs to implement dynamic and integrated control of spinal cord function.     

眼睛发育与骨形成蛋白信号通路的关系

在早期胚胎发育过程中,眼睛是由起源于不同胚层的几个部分经过一系列的诱导作用以及时间和空间上的相互协调作用形成的复杂而又具有精确功能的器官。在眼睛的形成发育过程中,许多信号通路及其相关的调控因子发挥着重要作用。本文主要关注眼睛发育过程与骨形成蛋白(BMP)信号通路的关系,BMP信号的激活能够诱导晶状体的再生和CLT(角膜到晶状体的分化转移)进程,维持睫状体的功能,促进视网膜的发生,影响巩膜的重塑和泪腺的发育。很多眼部疾病的发生与BMP信号通路的调节紊乱密切相关,因此可以将BMP信号通路作为一个潜在的药物靶点来探究治疗眼部疾病的方法。本文就BMP信号通路对眼睛发育的影响作一综述。     

Follistatin‐like 1 in vertebrate development

Follistatin‐like 1 (Fstl1) is a member of the secreted protein acidic rich in cysteins (SPARC) family and has been implicated in many different signaling pathways, including bone morphogenetic protein (BMP) signaling. In many different developmental processes like, dorso‐ventral axis establishment, skeletal, lung and ureter development, loss of function experiments have unveiled an important role for Fstl1. Fstl1 largely functions through inhibiting interactions with the BMP signaling pathway, although, in various disease models, different signaling pathways, like activation of pAKT, pAMPK, Na/K‐ATPase, or innate immune responses, are linked to Fstl1. How Fstl1 inhibits BMP signaling remains unclear, although it is known that Fstl1 does not function through a scavenging mechanism, like the other known extracellular BMP inhibitors such as noggin. It has been proposed that Fstl1 interferes with BMP receptor complex formation and as such inhibits propagation of the BMP signal into the cell. Future challenges will encompass the identification of the factors that determine the mechanisms that underlie the fact that Fstl1 acts by interfering with BMP signaling during development, but through other signaling pathways during disease. Birth Defects Research (Part C) 99:61–69, 2013. © 2013 Wiley Periodicals, Inc.     

Wnt, activin, and BMP signaling regulate distinct stages in the developmental pathway from embryonic stem cells to blood

The embryonic stem cell differentiation system was used to define the roles of the Activin/Nodal, BMP, and canonical Wnt signaling pathways at three distinct developmental stages during hematopoietic ontogeny: induction of a primitive streak-like population, formation of Flk1(+) mesoderm, and induction of hematopoietic progenitors. Activin/Nodal and Wnt, but not BMP, signaling are required for the induction of the primitive streak. Although BMP is not required for primitive streak induction, it displays a strong posteriorizing effect on this population. All three signaling pathways regulate induction of Flk1(+) mesoderm. The specification of Flk1(+) mesoderm to the hematopoietic lineages requires VEGF and Wnt, but not BMP or Activin/Nodal signaling. Specifically, Wnt signaling is essential for commitment of the primitive erythroid, but not the definitive lineages. These findings highlight dynamic changes in signaling requirements during blood cell development and identify a role for Wnt signaling in the establishment of the primitive erythroid lineage.     

Morphogen signaling at the vertebrate growth cone: a few cases or a general strategy?

Axon navigation relies on the competence of growth cones to sense and interpret attractive and repulsive guidance cues present along their trajectory. For most neurons, this process is mediated by a limited number of conserved families of ligand-receptor signaling systems, including Ephrin/Eph, Netrins/DCC-Unc5, Slits/Robo, and Semaphorins/Plexin-Neuropilin. Recent studies have demonstrated that some neurons respond also to well-known secreted signaling molecules, best known for their roles as morphogens, such as BMP7, SHH, FGF8, and Wnt. Thus, retina ganglion cell axon navigation is influenced by FGF, SHH, and possibly BMP signaling. Similarly, commissural neurons in the spinal cord respond sequentially to the activity of BMP, SHH, and Wnt to extend toward and away from their intermediate target, the floor plate. The data that support this conclusion will be summarized and how morphogens may signal at the growth cone will be discussed.     

Back and forth between cell fate specification and movement during vertebrate gastrulation

Animal body plan arises during gastrulation and organogenesis by the coordination of inductive events and cell movements. Several signaling pathways, such as BMP, FGF, Hedgehog, Nodal, and Wnt have well-recognized instructive roles in cell fate specification during vertebrate embryogenesis. Growing evidence indicates that BMP, Nodal, and FGF signaling also regulate cell movements, and that they do so through mechanisms distinct from those that specify cell fates. Moreover, pathways controlling cell movements can also indirectly influence cell fate specification by regulating dimensions and relative positions of interacting tissues. The current challenge is to delineate the molecular mechanisms via which the major signaling pathways regulate cell fate specification and movements, and how these two processes are coordinated to ensure normal development.