Abstract
Neural crest cells are multipotent progenitor cells that can generate both ectodermal cell types, such as neurons, and mesodermal cell types, such as smooth muscle. The mechanisms controlling this cell fate choice are not known. The basic Helix-loop-Helix (bHLH) transcription factor Twist1 is expressed throughout the migratory and post-migratory cardiac neural crest. Twist1 ablation or mutation of the Twist-box causes differentiation of ectopic neuronal cells, which molecularly resemble sympathetic ganglia, in the cardiac outflow tract. Twist1 interacts with the pro-neural factor Sox10 via its Twist-box domain and binds to the Phox2b promoter to repress transcriptional activity. Mesodermal cardiac neural crest trans-differentiation into ectodermal sympathetic ganglia-like neurons is dependent upon Phox2b function. Ectopic Twist1 expression in neural crest precursors disrupts sympathetic neurogenesis. These data demonstrate that Twist1 functions in post-migratory neural crest cells to repress pro-neural factors and thereby regulate cell fate determination between ectodermal and mesodermal lineages.
Highlights
Neural Crest Cells (NCCs) are multi-potent progenitor cells, which after delaminating from the dorsal lip of the neural tube and migrating throughout the developing embryo, can differentiate along either ectodermal or mesodermal lineages [1,2,3,4]
In situ hybridization analysis demonstrates that expression of Sox9, a transcriptional regulator of extracellular matrix (ECM) components, is abnormally absent from the aggregations, but is expressed normally within non-phenotypic cardiac NCCs (cNCCs)
The feature that distinguishes these cNCC aggregates from normal cNCC mesenchyme is the expression of Hand1 and Hand2, which accounts for approximately 30–40% of the cNCC within the E11.5 outflow tract (OFT) [14]
Summary
Neural Crest Cells (NCCs) are multi-potent progenitor cells, which after delaminating from the dorsal lip of the neural tube and migrating throughout the developing embryo, can differentiate along either ectodermal or mesodermal lineages [1,2,3,4]. NCCs are specified along a rostro-caudal axis into distinct subpopulations that have limited capacity to change their cell fate [10] Both the cardiac and the rostral-most vagal neural crest originate at the same axial level (somites 1–3), suggesting that additional mechanisms of cell fate determination beyond axial specification are necessary to distinguish these ectodermal and mesodermal lineages. Both differentiating sympathetic neurons and cNCCs have been shown to respond to local secreted signaling cues, notably Bone Morphogenetic Proteins (BMPs), subsequently upregulating transcriptional effectors such as the Twist family bHLH proteins, Hand and Hand, and initiating differentiation programs [11,12]. The mechanisms that enable post-migratory NCCs to interpret these local signaling cues and to undergo either ectodermal or mesodermal differentiation programs are not understood
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