HLH-2/E2A Expression Links Stochastic and Deterministic Elements of a Cell Fate Decision during C. elegans Gonadogenesis.

Stochastic mechanisms diversify cell fate in organisms ranging from bacteria to humans [ 1–4 ]. In the anchor cell/ventral uterine precursor cell (AC/VU) fate decision during C. elegans gonadogenesis, two "α cells," each with equal potential to be an AC or a VU, interact via LIN-12/Notch and its ligand LAG-2/DSL [ 5, 6 ]. This LIN-12/Notch-mediated interaction engages feedback mechanisms that amplify a stochastic initial difference between the two α cells, ensuring that the cell with higher lin-12 activity becomes the VU while the other becomes the AC [ 7–9 ]. The initial difference between the α cells was originally envisaged as a random imbalance from "noise" in lin-12 expression/activity [ 6 ]. However, subsequent evidence that the relative birth order of the α cells biases their fates suggested other factors may be operating [ 7 ]. Here, we investigate the nature of the initial difference using high-throughput lineage analysis [ 10 ]; GFP-tagged endogenous LIN-12, LAG-2, and HLH-2, a conserved transcription factor that orchestrates AC/VU development [ 7, 11 ]; and tissue-specific hlh-2 null alleles. We identify two stochastic elements: relative birth order, which largely originates at the beginning of the somatic gonad lineage three generations earlier, and onset of HLH-2 expression, such that the α cell whose parent expressed HLH-2 first is biased toward the VU fate. We find that these elements are interrelated, because initiation of HLH-2 expression is linked to the birth of the parent cell. Finally, we provide a potential deterministic mechanism for the HLH-2 expression bias by showing that hlh-2 is required for LIN-12 expression in the α cells. • LIN-12/Notch resolves a stochastic cell fate decision of two equipotential α cells • Two stochastic events bias their fates: relative birth order and HLH-2 expression • Onset of HLH-2 expression is linked to the birth of the parents of the α cells • LIN-12 expression requires HLH-2: a potential deterministic decision mechanism Two bipotential α cells interact via LIN-12/Notch and its ligand LAG-2/DSL, engaging feedback mechanisms that amplify a stochastic initial difference between them. Attner et al. identify two interrelated stochastic elements and provide a potential deterministic mechanism by showing that hlh-2 is required for LIN-12 expression in the α cells. [ABSTRACT FROM AUTHOR]