The precise timing of distinct cellular events is fundamental to organismal development. In C. elegans temporal selector genes, called heterochronic loci, regulate stage specific cellular programs during larval development. Many heterochronic genes are evolutionarily conserved and control temporal patterning of cell division, migration and differentiation events across taxa.
dre-1 specifies C. elegans late larval development by preventing precocious expression of adult specific seam cell fates, and encodes a highly conserved F-Box protein orthologous to human FBXO11 (Fielenbach et al., Dev Cell 2007). F-box proteins function as substrate recognition components of SCF E3-ubiquitin ligase complexes. Recently, Pagano and colleagues identified two substrates of human FBXO11: BCL-6 (Duan et al., Nature 2012) and CDT-2 (Rossi et al., Mol Cell 2013). However, the DRE-1/FBXO11 substrate(s) involved in developmental timing remains largely unknown. From RNAi-based suppressor screens, we identified the Zn finger transcription factor BLMP-1 as a novel substrate of the SCFDRE-1/FBXO11 E3-ubiquitin ligase complex.
blmp-1 depletion strongly suppressed
dre-1 mutant developmental timing defects as well as those of other precocious heterochronic loci such as
hbl-1,
lin-41 and
lin-42.
blmp-1 loss of function mutants showed alterations in seam cell fates and gonadal outgrowth establishing
blmp-1 as a heterochronic gene. Consistent with BLMP-1 being a DRE-1 substrate, BLMP-1 protein levels were strikingly elevated upon
dre-1 depletion.
blmp-1::GFP expression was regulated in a stage and tissue specific manner consistent with the corresponding phenotypes. Importantly DRE-1 and BLMP-1 protein interacted in vivo, and the mammalian counterparts co-precipitated in cell culture, revealing an evolutionary conserved interaction between these two proteins. Mammalian BLIMP1 is the key determinant of B cell maturation and has been implicated in stem cell biology and cancer. Our studies show that post-translational regulation of C. elegans BLMP-1 by DRE-1/FBXO11 is critical for coordination of developmental timing and maturation, suggesting that these two proteins may work together to regulate related processes throughout taxa.