title: Transcriptional establishment of cell-type identity: dynamics and causal mechanisms of T-cell lineage commitment.
abstract: Precursor cell entry into the T-cell developmental pathway can be divided into two phases by the closure of T-lineage commitment. As cells decide against the last alternative options to the T-cell fate, they turn on the transcription factor Bcl11b and silence expression of a group of multipotent progenitor regulatory factors that include hematopoietic transcription factor PU.1. Functional perturbation tests show that Bcl11b is needed for commitment while PU.1 actively participates in keeping open access to alternative fates, until it is silenced; however, PU.1 and Bcl11b both contribute positively to T-cell development. Our recent work reviewed here sheds light on the transcriptional regulatory network that determines the timing and irreversibility of Bcl11b activation, the ways that Notch signaling from the thymic microenvironment restricts the action of PU.1 to prevent it from diverting cells to non-T fates, and the target genes that PU.1 still regulates under the influence of Notch signaling to contribute to T-cell generation. We argue that T-cell development depends on the sequential operation of two interlaced, but mutually antagonistic, gene regulatory networks, one initially supporting expansion before commitment and the other imposing a "terminal" differentiation process on committed cells.
authors.affiliation: Division of Biology 156-29, California Institute of Technology, Pasadena, California 91125 evroth@its.caltech.edu.
authors.forename: Ellen V
authors.initials: EV
authors.lastname: Rothenberg
authors.affiliation: Division of Biology 156-29, California Institute of Technology, Pasadena, California 91125.
authors.forename: Ameya
authors.initials: A
authors.lastname: Champhekar
authors.affiliation: Division of Biology 156-29, California Institute of Technology, Pasadena, California 91125.
authors.forename: Sagar
authors.initials: S
authors.lastname: Damle
authors.affiliation: Division of Biology 156-29, California Institute of Technology, Pasadena, California 91125.
authors.forename: Marissa Morales
authors.initials: MM
authors.lastname: Del Real
authors.affiliation: Division of Biology 156-29, California Institute of Technology, Pasadena, California 91125.
authors.forename: Hao Yuan
authors.initials: HY
authors.lastname: Kueh
authors.affiliation: Division of Biology 156-29, California Institute of Technology, Pasadena, California 91125.
authors.forename: Long
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Biology 156-29, California Institute of Technology, Pasadena, California 91125.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Yui
mesh_terms: D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage; D053263:Gene Regulatory Networks; D005799:Genes, Dominant; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D016896:Treatment Outcome; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D011518:Proto-Oncogene Proteins; D051880:Receptors, Notch; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1