Asymmetric activation of Dll4-Notch signaling by Foxn4 and proneural factors activates BMP/TGFβ signaling to specify V2b interneurons in the spinal cord
0301 basic medicine
0303 health sciences
Calcium-Binding Proteins
Intracellular Signaling Peptides and Proteins
Gene Expression Regulation, Developmental
Membrane Proteins
Cell Differentiation
Forkhead Transcription Factors
Nerve Tissue Proteins
Chick Embryo
3. Good health
Mice, Inbred C57BL
Mice
03 medical and health sciences
Neural Stem Cells
Interneurons
Bone Morphogenetic Proteins
Basic Helix-Loop-Helix Transcription Factors
Animals
Cell Lineage
RNA Interference
RNA, Small Interfering
Eye Proteins
10. No inequality
Adaptor Proteins, Signal Transducing
DOI:
10.1242/dev.092536
Publication Date:
2013-11-21T02:44:48Z
AUTHORS (5)
ABSTRACT
During development of the ventral spinal cord, the V2 interneurons emerge from p2 progenitors and diversify into two major subtypes, V2a and V2b, that play key roles in locomotor coordination. Dll4-mediated Notch activation in a subset of p2 precursors constitutes the crucial first step towards generating neuronal diversity in this domain. The mechanism behind the asymmetric Notch activation and downstream signaling events are, however, unknown at present. We show here that the Ascl1 and Neurog basic helix-loop-helix (bHLH) proneural factors are expressed in a mosaic pattern in p2 progenitors and that Foxn4 is required for setting and maintaining this expression mosaic. By binding directly to a conserved Dll4 enhancer, Foxn4 and Ascl1 activate Dll4 expression, whereas Neurog proteins prevent this effect, thereby resulting in asymmetric activation of Dll4 expression in V2 precursors expressing different combinations of proneural and Foxn4 transcription factors. Lineage tracing using the Cre-LoxP system reveals selective expression of Dll4 in V2a precursors, whereas Dll4 expression is initially excluded from V2b precursors. We provide evidence that BMP/TGFβ signaling is activated in V2b precursors and that Dll4-mediated Notch signaling is responsible for this activation. Using a gain-of-function approach and by inhibiting BMP/TGFβ signal transduction with pathway antagonists and RNAi knockdown, we further demonstrate that BMP/TGFβ signaling is both necessary and sufficient for V2b fate specification. Our data together thus suggest that the mosaic expression of Foxn4 and proneural factors may serve as the trigger to initiate asymmetric Dll4-Notch and subsequent BMP/TGFβ signaling events required for neuronal diversity in the V2 domain.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (69)
CITATIONS (38)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....