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    Reiser LabProject Technical Resources
    01/05/24 | Homeodomain proteins hierarchically specify neuronal diversity and synaptic connectivity
    Chundi Xu , Tyler B. Ramos , Ed M. Rogers , Michael B. Reiser , Chris Q. Doe
    eLife. 2024 Jan 05:. doi: 10.7554/eLife.90133

    The brain generates diverse neuron types which express unique homeodomain transcription factors (TFs) and assemble into precise neural circuits. Yet a mechanistic framework is lacking for how homeodomain TFs specify both neuronal fate and synaptic connectivity. We use Drosophila lamina neurons (L1-L5) to show the homeodomain TF Brain-specific homeobox (Bsh) is initiated in lamina precursor cells (LPCs) where it specifies L4/L5 fate and suppresses homeodomain TF Zfh1 to prevent L1/L3 fate. Subsequently, Bsh activates the homeodomain TF Apterous (Ap) in L4 in a feedforward loop to express the synapse recognition molecule DIP-β, in part by Bsh direct binding a DIP-β intron. Thus, homeodomain TFs function hierarchically: primary homeodomain TF (Bsh) first specifies neuronal fate, and subsequently acts with secondary homeodomain TF (Ap) to activate DIP-β, thereby generating precise synaptic connectivity. We speculate that hierarchical homeodomain TF function may represent a general principle for coordinating neuronal fate specification and circuit assembly.

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