A universal transportin protein drives stochastic choice of olfactory neurons via specific nuclear import of a <i>sox-2</i>-activating factor.

Abstract

Stochastic neuronal cell fate choice involving notch-independent mechanisms is a poorly understood biological process. The <i>Caenorhabditis elegans</i> AWC olfactory neuron pair asymmetrically differentiates into the default AWC^OFF and induced AWC^ON subtypes in a stochastic manner. Stochastic choice of the AWC^ON subtype is established using gap junctions and SLO BK potassium channels to repress a calcium-activated protein kinase pathway. However, it is unknown how the potassium channel-repressed calcium signaling is translated into the induction of the AWC^ON subtype. Here, we identify a detailed working mechanism of how the homeodomain-like transcription factor NSY-7, previously described as a repressor in the maintenance of AWC asymmetry, couples SLO BK potassium channels to transactivation of <i>sox-2</i> expression for the induction of the AWC^ON subtype through the identification of a unique <i>imb-2</i> (transportin 1) allele. <i>imb-2</i> loss-of-function mutants are not viable; however, we identify a viable <i>imb-2</i> allele from an unbiased forward genetic screen that reveals a specific role of <i>imb-2</i> in AWC olfactory neuron asymmetry. IMB-2 specifically drives nuclear import of NSY-7 within AWC neurons to transactivate the expression of the high mobility group (HMG)-box transcription factor SOX-2 for the specification of the AWC^ON subtype. This study provides mechanistic insight into how NSY-7 couples SLO BK potassium channels to transactivation of <i>sox-2</i> expression for the induction of the AWC^ON subtype. Our findings also provide structure-function insight into a conserved amino acid residue of transportins in brain development and suggest its dysfunction may lead to human neurological disorders.