Image_3_Foxa2 and Pet1 Direct and Indirect Synergy Drive Serotonergic Neuronal Differentiation.pdf
Neuronal programming by forced expression of transcription factors (TFs) holds promise for clinical applications of regenerative medicine. However, the mechanisms by which TFs coordinate their activities on the genome and control distinct neuronal fates remain obscure. Using direct neuronal programming of embryonic stem cells, we dissected the contribution of a series of TFs to specific neuronal regulatory programs. We deconstructed the Ascl1-Lmx1b-Foxa2-Pet1 TF combination that has been shown to generate serotonergic neurons and found that stepwise addition of TFs to Ascl1 canalizes the neuronal fate into a diffuse monoaminergic fate. The addition of pioneer factor Foxa2 represses Phox2b to induce serotonergic fate, similar to in vivo regulatory networks. Foxa2 and Pet1 appear to act synergistically to upregulate serotonergic fate. Foxa2 and Pet1 co-bind to a small fraction of genomic regions but mostly bind to different regulatory sites. In contrast to the combinatorial binding activities of other programming TFs, Pet1 does not strictly follow the Foxa2 pioneer. These findings highlight the challenges in formulating generalizable rules for describing the behavior of TF combinations that program distinct neuronal subtypes.
History
Usage metrics
Categories
- Radiology and Organ Imaging
- Decision Making
- Autonomic Nervous System
- Cellular Nervous System
- Biological Engineering
- Central Nervous System
- Sensory Systems
- Neuroscience
- Endocrinology
- Artificial Intelligence and Image Processing
- Clinical Nursing: Tertiary (Rehabilitative)
- Image Processing
- Signal Processing
- Rehabilitation Engineering
- Biomedical Engineering not elsewhere classified
- Stem Cells
- Neurogenetics
- Developmental Biology