Journal
BIOINFORMATICS
Volume 27, Issue 22, Pages 3158-3165Publisher
OXFORD UNIV PRESS
DOI: 10.1093/bioinformatics/btr551
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Funding
- National Natural Science Foundation of China [11171206, 91029301, 61134013, 10832006, 61072149]
- Shanghai Municipal Education Commission [12YZ030]
- CAS [KSCX2-EW-R-01]
- SIBS of CAS [2009CSP002]
- Shanghai Pujiang Program [11PJ1410500]
- National Center for Mathematics and Interdisciplinary Sciences, CAS
- Japan Society for the Promotion of Science (JSPS)
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Motivation: In the developing nervous system, the expression of proneural genes, i.e. Hes1, Neurogenin-2 (Ngn2) and Deltalike-1 (Dll1), oscillates in neural progenitors with a period of 2-3 h, but is persistent in post-mitotic neurons. Unlike the synchronization of segmentation clocks, oscillations in neural progenitors are asynchronous between cells. It is known that Notch signaling, in which Notch in a cell can be activated by Dll1 in neighboring cells (trans-activation) and can also be inhibited by Dll1 within the same cell (cis-inhibition), is important for neural fate decisions. There have been extensive studies of trans-activation, but the operating mechanisms and potential implications of cis-inhibition are less clear and need to be further investigated. Results: In this article, we present a computational model for neural fate decisions based on intertwined dynamics with trans-activation and cis-inhibition involving the Hes1, Notch and Dll1 proteins. In agreement with experimental observations, the model predicts that both trans-activation and cis-inhibition play critical roles in regulating the choice between remaining as a progenitor and embarking on neural differentiation. In particular, trans-activation is essential for generation of oscillations in neural progenitors, and cis-inhibition is important for the asynchrony between adjacent cells, indicating that the asynchronous oscillations in neural progenitors depend on cooperation between trans-activation and cis-inhibition. In contrast, cis-inhibition plays more critical roles in embarking on neural differentiation by inactivating intercellular Notch signaling. The model presented here might be a good candidate for providing the first qualitative mechanism of neural fate decisions mediated by both trans-activation and cis-inhibition.
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