BCL-11 enables adaptive stress responses to environmental challenges

Insulin/IGF-1 signaling (IIS) is a master regulator of metabolism, stress resilience, and cell homeostasis in multicellular organisms. In the nematode <i>Caenorhabditis elegans</i>, DAF-2 regulates dauer diapause, animal growth, and lifespan extension in a DAF-16/FOXO-dependent manner. Here we investigated IIS in animals expressing pathogenic variants of BCL-11, an evolutionarily conserved transcription factor that has been implicated in human neurodevelopmental disorders. We found that hypomorphic <i>bcl-11</i> mutations have a limited impact on <i>C</i>. <i>elegans</i> growth and survival under standard growth conditions. On the contrary, BCL-11 deficiency compromises the cytoprotective properties of <i>daf-2</i> signaling upon animal exposure to stress. During embryonic development, <i>daf-16</i> loss of function rescues egg hatching defects in <i>daf-2;bcl-11</i> mutants, suggesting a transcriptional interplay between BCL-11 and DAF-16 in IIS-deficient animals. Together, our data suggest that BCL-11 actively regulates transcription during development, while in adult animals it is recruited in response to environmental insults to enhance stress resilience.