Contingent gene regulatory networks and B cell fate specification

Abstract

The B cell developmental pathway represents a leading system for the analysis of regulatory circuits that orchestrate cell fate specification and commitment. Considerable progress has been achieved within the past decade in the identification and genetic analysis of various regulatory components. These components include the transcription factors PU.1, Ikaros, Bcl11a, E2A, EBF, and Pax-5, as well as the cytokine receptors Flk2 and IL-7R. Experimental evidence of connectivity among the regulatory components is used to assemble sequentially acting and contingent gene regulatory networks. Transient signaling inputs, self-sustaining positive feedback loops, and cross-antagonism among alternate cell fate determinants are key features of the proposed networks that instruct the development of B lymphocyte precursors from hematopoietic stem cells.

Fig. 1.

Gene regulatory networks that direct the generation of a B cell precursor from a HSC. Four successive, interdependent developmental states are depicted. Each transition involves distinct combinations of regulatory molecules: gene regulatory proteins (e.g., PU.1) and signaling receptors (e.g., IL-7R). Gene regulators activate or repress target genes, whereas signaling receptors induce or modify the activities of gene regulators. CD19 is a B lineage-specific cell surface protein (Ig coreceptor component) that signifies commitment to the B cell fate. Regulatory connections are shown as dashed or solid arrows, depending on the strength of the supportive experimental evidence.

Fig. 2.

Gene expression programs activated in specified pro-B cells and their differentiated progeny (B cell precursors). E2A-, EBF-, and Pax-5-regulated genes and IgH locus DNA rearrangements are shown. Pax-5 expression is contingent on E2A and EBF. Pax-5 reinforces and expands the B lineage program of gene expression. E2A* indicates E2A activation.

Fig. 3.

A self-sustaining regulatory network established in a B cell precursor. It is suggested that the establishment of this network depends on transient signaling and inputs from the cytokine receptor Flk2 and the transcription factors PU.1 and Ikaros, respectively. Positive feedback loops involving the cytokine receptor IL-7R and the transcription factors EBF, E2A, and Pax-5 may generate a self-sustaining circuit. The network architecture also features crossantagonism with alternate cell fate-determining transcription factors such as GATA-1, C/EBPα, and Notch-1. Stimulatory and inhibitory inputs are indicated as solid or dashed lines, depending on the strength of the experimental evidence.