Neural crest-related NXPH1/α-NRXN signaling opposes neuroblastoma malignancy by inhibiting organotropic metastasis.

Neuroblastoma is a pediatric cancer that can present as low- or high-risk tumors (LR-NBs and HR-NBs), the latter group showing poor prognosis due to metastasis and strong resistance to current therapy. Whether LR-NBs and HR-NBs differ in the way they exploit the transcriptional program underlying their neural crest, sympatho-adrenal origin remains unclear. Here, we identified the transcriptional signature distinguishing LR-NBs from HR-NBs, which consists mainly of genes that belong to the core sympatho-adrenal developmental program and are associated with favorable patient prognosis and with diminished disease progression.

BuMPing Into Neurogenesis: How the Canonical BMP Pathway Regulates Neural Stem Cell Divisions Throughout Space and Time.

Bone morphogenetic proteins (BMPs) are secreted factors that contribute to many aspects of the formation of the vertebrate central nervous system (CNS), from the initial shaping of the neural primordium to the maturation of the brain and spinal cord. In particular, the canonical (SMAD1/5/8-dependent) BMP pathway appears to play a key role during neurogenesis, its activity dictating neural stem cell fate decisions and thereby regulating the growth and homeostasis of the CNS. In this mini-review, I summarize accumulating evidence demonstrating how the canonical BMP activity promotes the amplification and/or maintenance of neural stem cells at different times and in diverse regions of the vertebrate CNS, and highlight findings suggesting that this function is evolutionarily conserved.

A SMAD1/5-YAP signalling module drives radial glia self-amplification and growth of the developing cerebral cortex.

The growth and evolutionary expansion of the cerebral cortex are defined by the spatial-temporal production of neurons, which itself depends on the decision of radial glial cells (RGCs) to self-amplify or to switch to neurogenic divisions. The mechanisms regulating these RGC fate decisions are still incompletely understood. Here, we describe a novel and evolutionarily conserved role of the canonical BMP transcription factors SMAD1/5 in controlling neurogenesis and growth during corticogenesis.

E proteins sharpen neurogenesis by modulating proneural bHLH transcription factors' activity in an E-box-dependent manner.

Class II HLH proteins heterodimerize with class I HLH/E proteins to regulate transcription. Here, we show that E proteins sharpen neurogenesis by adjusting the neurogenic strength of the distinct proneural proteins. We find that inhibiting BMP signaling or its target ID2 in the chick embryo spinal cord, impairs the neuronal production from progenitors expressing ATOH1/ASCL1, but less severely that from progenitors expressing NEUROG1/2/PTF1a.

The strength of SMAD1/5 activity determines the mode of stem cell division in the developing spinal cord.

The different modes of stem cell division are tightly regulated to balance growth and differentiation during organ development and homeostasis. However, the mechanisms controlling such events are not fully understood. We have developed markers that provide the single cell resolution necessary to identify the three modes of division occurring in a developing nervous system: self-expanding, self-renewing, and self-consuming.

Sonic hedgehog signaling switches the mode of division in the developing nervous system.

The different modes of stem cell division are tightly regulated to balance growth and differentiation during organ development and homeostasis, and these regulatory processes are subverted in tumor formation. Here, we developed markers that provided the single-cell resolution necessary to quantify the three modes of division taking place in the developing nervous system in vivo: self-expanding, PP; self-replacing, PN; and self-consuming, NN. Using these markers and a mathematical model that predicts the dynamics of motor neuron progenitor division, we identify a role for the morphogen Sonic hedgehog in the maintenance of stem cell identity in the developing spinal cord.

The multiple activities of BMPs during spinal cord development.

Bone morphogenetic proteins (BMPs) are one of the main classes of multi-faceted secreted factors that drive vertebrate development. A growing body of evidence indicates that BMPs contribute to the formation of the central nervous system throughout its development, from the initial shaping of the neural primordium to the generation and maturation of the different cell types that form the functional adult nervous tissue. In this review, we focus on the multiple activities of BMPs during spinal cord development, paying particular attention to recent results that highlight the complexity of BMP signaling during this process.

Temporal control of BMP signalling determines neuronal subtype identity in the dorsal neural tube.

The conventional explanation for how a morphogen patterns a tissue holds that cells interpret different concentrations of an extrinsic ligand by producing corresponding levels of intracellular signalling activity, which in turn regulate differential gene expression. However, this view has been challenged, raising the possibility that distinct mechanisms are used to interpret different morphogens. Here, we investigate graded BMP signalling in the vertebrate neural tube.

LMO4 is an essential cofactor in the Snail2-mediated epithelial-to-mesenchymal transition of neuroblastoma and neural crest cells.

Neuroblastoma is an embryonic tumor derived from cells of the neural crest. Taking advantage of a newly developed neural crest lineage tracer and based on the hypothesis that the molecular mechanisms that mediate neural crest delamination are also likely to be involved in the spread of neuroblastoma, we were able to identify genes that are active both in neural crest development and neuroblastoma tumor formation. A subsequent search of the neuroblastoma gene server for human orthologues of genes differentially expressed in the chick embryo neural crest screen retrieved the LIM domain only protein 4 (LMO4), which was expressed in both cell types analyzed.

Dorsal-ventral patterning of the neural tube: a tale of three signals.

Development of the vertebrate nervous system begins with the acquisition of neural identity from the midline dorsal-ectodermal cells of the gastrulating embryos. The subsequent progressive specification of the neural plate along its anterior-posterior and dorsal-ventral (DV) axes allows the generation of the tremendous variety of neuronal and glial cells that compose the vertebrate central nervous system (CNS). Studies on the development of the spinal cord, the anatomically simplest part of the CNS, have generated most of our current knowledge on the signaling events and the genetic networks that orchestrate the DV patterning of the neural plate.

Canonical BMP7 activity is required for the generation of discrete neuronal populations in the dorsal spinal cord.

BMP activity is essential for many steps of neural development, including the initial role in neural induction and the control of progenitor identities along the dorsal-ventral axis of the neural tube. Taking advantage of chick in ovo electroporation, we show a novel role for BMP7 at the time of neurogenesis initiation in the spinal cord. Using in vivo loss-of-function experiments, we show that BMP7 activity is required for the generation of three discrete subpopulations of dorsal interneurons: dI1-dI3-dI5.

Temporal and spatial expression of CCN3 during retina development.

NOV/CCN3 is one of the founding members of the CCN (Cyr61 CTGF NOV) family. In the avian retina, CCN3 expression is mostly located within the central region of the inner nuclear layer. As retinal development progresses and this retinal layer differentiates and matures, CCN3 expression forms a dorsal-ventral and a central-peripheral gradient.

Hedgehog activation is required upstream of Wnt signalling to control neural progenitor proliferation.

The canonical Wnt and sonic hedgehog (Shh) pathways have been independently linked to cell proliferation in a variety of tissues and systems. However, interaction of these signals in the control of cell cycle progression has not been studied. Here, we demonstrate that in the developing vertebrate nervous system these pathways genetically interact to control progression of the G1 phase of the cell cycle.

NOV/CCN3 impairs muscle cell commitment and differentiation.

NOV (nephroblastoma overexpressed) is a member of a family of proteins which encodes secreted matrix-associated proteins. NOV is expressed during development in dermomyotome and limb buds, but its functions are still poorly defined. In order to understand the role of NOV in myogenic differentiation, C2C12 cells overexpressing NOV (C2-NOV) were generated.

New target genes for NOV/CCN3 in chondrocytes: TGF-beta2 and type X collagen.

Unlabelled: We studied the involvement of NOV/CCN3, whose function is poorly understood, in chondrocyte differentiation. NOV was found to upregulate TGF-beta2 and type X collagen and to act as a downstream effector of TGF-beta1 in ATDC5 and primary chondrocytes. Thus, NOV is a positive modulator of chondrogenesis.