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Published May 2016 | Accepted Version
Journal Article Open

Hematopoiesis and T-cell specification as a model developmental system

Abstract

The pathway to generate T cells from hematopoietic stem cells guides progenitors through a succession of fate choices while balancing differentiation progression against proliferation, stage to stage. Many elements of the regulatory system that controls this process are known, but the requirement for multiple, functionally distinct transcription factors needs clarification in terms of gene network architecture. Here, we compare the features of the T-cell specification system with the rule sets underlying two other influential types of gene network models: first, the combinatorial, hierarchical regulatory systems that generate the orderly, synchronized increases in complexity in most invertebrate embryos; second, the dueling 'master regulator' systems that are commonly used to explain bistability in microbial systems and in many fate choices in terminal differentiation. The T-cell specification process shares certain features with each of these prevalent models but differs from both of them in central respects. The T-cell system is highly combinatorial but also highly dose-sensitive in its use of crucial regulatory factors. The roles of these factors are not always T-lineage-specific, but they balance and modulate each other's activities long before any mutually exclusive silencing occurs. T-cell specification may provide a new hybrid model for gene networks in vertebrate developmental systems.

Additional Information

© 2016 John Wiley & Sons. Article first published online: 18 APR 2016. We gratefully acknowledge the late Eric Davidson for stimulating discussions of developmental gene network properties in diverse systems. We thank past and present members of the Rothenberg and Michael Elowitz groups for valuable advice and sharing of unpublished results, Maria Lerica Gutierrez Quiloan for mouse colony supervision, and Rochelle Diamond, Keith Beadle, and Diana Perez for flow cytometry. The ideas presented here were developed with support by grants from NIH: RC2CA148278, R01AI083514, R01AI095943, R01CA90233, R01HD076915 and R01HL119102 to E. V. R., R01AI064590 to M. A. Y., and K99HL119638A to H. Y. K.; also by the L. A. Garfinkle Memorial Laboratory Fund, and by the Albert Billings Ruddock Professorship to E. V. R. None of the authors has a conflict of interest.

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August 20, 2023
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