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

Dréau, Gwenvaël Le; García‐Campmany, Lidia; Rabadán, M. Angeles; Ferronha, Tiago; Tozer, Samuel; Briscoe, James; Martı́, Elisa

doi:10.1242/dev.074948

Cited by 80 publications

(115 citation statements)

References 43 publications

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“…The majority of BMPs have specific functions in neurogenesis, BMP-2 is crucial in gliogenesis [18, 19]. Mainly, when telencephalic neural progenitors are exposed to BMP-2, their developmental fate is switched to the astrocytic cell lineage [20, 21].…”

Section: Introductionmentioning

confidence: 99%

Co-evolution of breast-to-brain metastasis and neural progenitor cells

Neman

Choy

Kowolik

et al. 2013

Clin Exp Metastasis

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Brain colonization by metastatic tumor cells offers a unique opportunity to investigate microenvironmental influences on the neoplastic process. The bi-directional interplay of breast cancer cells (mesodermal origin) and brain cells (neuroectodermal origin) is poorly understood and rarely investigated. In our patients undergoing neurosurgical resection of breast-to-brain metastases, specimens from the tumor/brain interface exhibited increased active gliosis as previously described. In addition, our histological characterization revealed infiltration of neural progenitor cells (NPCs) both outside and inside the tumor margin, leading us to investigate the cellular and molecular interactions between NPCs and metastases. Since signaling by the TGF-β superfamily is involved in both developmental neurobiology and breast cancer pathogenesis, we examined the role of these proteins in the context of brain metastases. The brain-metastatic breast cancer cell line MDA-MB-231Br (231Br) expressed BMP-2 at significantly higher levels compared to its matched primary breast cancer cell line MDA-MB-231 (231). Co-culturing was used to examine bi-directional cellular effects and the relevance of BMP-2 overexpression. When co-cultured with NPCs, 231 (primary) tumor cells failed to proliferate over 15 days. However, 231Br (brain meta-static) tumor cells co-cultured with NPCs escaped growth inhibition after day 5 and proliferated, occurring in parallel with NPC differentiation into astrocytes. Using shRNA and gene knock-in, we then demonstrated BMP-2 secreted by 231Br cells mediated NPC differentiation into astrocytes and concomitant tumor cell proliferation in vitro. In xenografts, overexpression of BMP-2 in primary breast cancer cells significantly enhanced their ability to engraft and colonize the brain, thereby creating a metastatic phenotype. Conversely, BMP-2 knockdown in metastatic breast cancer cells significantly diminished engraftment and colonization. The results suggest metastatic tumor cells create a permissive neural niche by steering NPC differentiation toward astrocytes through paracrine BMP-2 signaling.

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Section: Introductionmentioning

confidence: 99%

Co-evolution of breast-to-brain metastasis and neural progenitor cells

Neman

Choy

Kowolik

et al. 2013

Clin Exp Metastasis

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“…This signaling cascade can be blocked by the inhibitory (I) Smads, Smad6 and Smad7 (Imamura et al, 1997; Nakao et al, 1997). Previous studies examining the role of the Smads establishing neural circuitry in the chicken spinal cord have shown that Smad1, Smad5 and Smad4 are critical for pattern formation in the dorsal neural tube (Chesnutt et al, 2004; Le Dreau et al, 2012). Moreover, we recently demonstrated that the I-Smads have distinct functions spatially limiting the response of dorsal cells to BMP signaling (Hazen et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

BMP receptor-activated Smads confer diverse functions during the development of the dorsal spinal cord

Hazen

Andrews

Umans

et al. 2012

Developmental Biology

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Bone Morphogenetic Proteins (BMPs) have multiple activities in the developing spinal cord: they specify the identity of the dorsal-most neuronal populations and then direct the trajectories of dorsal interneuron (dI) 1 commissural axons. How are these activities decoded by dorsal neurons to result in different cellular outcomes? Our previous studies have shown that the diverse functions of the BMPs are mediated by the canonical family of BMP receptors and then regulated by specific inhibitory (I) Smads, which block the activity of a complex of Smad second messengers. However, the extent to which this complex translates the different activities of the BMPs in the spinal cord has remained unresolved. Here, we demonstrate that the receptor-activated (R) Smads, Smad1 and Smad5 play distinct roles mediating the abilities of the BMPs to direct cell fate specification and axon outgrowth. Smad1 and Smad5 occupy spatially distinct compartments within the spinal cord, with Smad5 primarily associated with neural progenitors and Smad1 with differentiated neurons. Consistent with this expression profile, loss of function experiments in mouse embryos reveal that Smad5 is required for the acquisition of dorsal spinal neuron identities whereas Smad1 is critical for the regulation of dI1 axon outgrowth. Thus the R-Smads, like the I-Smads, have discrete roles mediating BMP-dependent cellular processes during spinal interneuron development.

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“…However, this model was proposed largely by analogy with the patterning events in the ventral spinal cord. There are many BMPs present in the roof plate (Butler and Dodd, 2003; Liem et al, 1997) and studies have also suggested that some of them have specific effects on the induction of particular neural fates (Le Dreau et al, 2012; Lee et al, 1998). An additional four classes of INs (dI4 to dI6, dIL) arise independently from signals from the roof plate; their identity may be dependent on signals from the adjacent paraxial mesoderm (Le Dreau and Marti, 2013).…”

Section: The Molecular and Cellular Organization Of Spinal Cordmentioning

confidence: 99%

From classical to current: Analyzing peripheral nervous system and spinal cord lineage and fate

Butler

Bronner‐Fraser

2015

Developmental Biology

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During vertebrate development, the central (CNS) and peripheral nervous systems (PNS) arise from the neural plate. Cells at the margin of the neural plate give rise to neural crest cells, which migrate extensively throughout the embryo, contributing to the majority of neurons and all of the glia of the PNS. The rest of the neural plate invaginates to form the neural tube, which expands to form the brain and spinal cord. The emergence of molecular cloning techniques and identification of fluorophores like Green Fluorescent Protein (GFP), together with transgenic and electroporation technologies, have made it possible to easily visualize the cellular and molecular events in play during nervous system formation. These lineage-tracing techniques have precisely demonstrated the migratory pathways followed by neural crest cells and increased knowledge about their differentiation into PNS derivatives. Similarly, in the spinal cord, lineage-tracing techniques have led to a greater understanding of the regional organization of multiple classes of neural progenitor and post-mitotic neurons along the different axes of the spinal cord and how these distinct classes of neurons assemble into the specific neural circuits required to realize their various functions. Here, we review how both classical and modern lineage and marker analyses have expanded our knowledge of early peripheral nervous system and spinal cord development.

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

Cited by 80 publications

References 43 publications

Co-evolution of breast-to-brain metastasis and neural progenitor cells

Co-evolution of breast-to-brain metastasis and neural progenitor cells

BMP receptor-activated Smads confer diverse functions during the development of the dorsal spinal cord

From classical to current: Analyzing peripheral nervous system and spinal cord lineage and fate

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