An adult-stage transcriptional program for survival of serotonergic connectivity

Neurons must function for decades of life but how these non-dividing cells are preserved is poorly understood. Using mouse serotonin (5-HT) neurons as a model, we discovered a novel adult-stage transcriptional program specialized to ensure the preservation of serotonergic connectivity. We uncover a switch in Lmx1b and Pet1 transcription factor function from controlling embryonic axonal growth to sustaining a transcriptomic signature of serotonergic connectivity comprising functionally diverse synaptic and axonal genes. Adult-stage deficiency of Lmx1b and Pet1 caused slowly progressive degeneration of 5-HT synapses and axons, increased susceptibility of 5-HT axons to neurotoxic injury, and abnormal stress responses. Axon degeneration occurred in a die back pattern and was accompanied by accumulation of alpha-synuclein and APP in spheroids and mitochondrial fragmentation without cell body loss. Our findings suggest neuronal connectivity is transcriptionally protected by maintenance of connectivity transcriptomes; progressive decay of such transcriptomes may contribute to age-related diseases of brain circuitry. 5-HT neuron RNA-seq profiles of control (iCON), Pet1CKO, Lmx1bCKO, and Pet1/Lmx1b DKO at 10 days and 1 month post-tamoxifen were generated by deep sequencing, in triplicate, using Illumina HiSeq 550. The sequence reads that passed quality filters were mapped to the UCSC mm10 mouse genome using Hisat2.