The long noncoding RNA Dory is required for female but not male spatial learning and memory

Large numbers of long noncoding RNAs (lncRNAs) exhibit region- or cell-specific expression and subcellular locations in the mammalian brain. We analyzed the expression and function of the mouse lncRNA 2700046G09Rik (also called Sgms1os1), which we have named Dory due to sex-specific disruption of spatial memory in rodent gene knockout and RNA knockdown. We show that Dory is predominantly expressed in a punctate pattern in nuclei of excitatory neurons in the hippocampus, and in both neuronal and non-neuronal cells in the cerebellum. We show by high resolution RNA sequencing that Dory brain transcripts are composed of 1-3 exons with multiple isoforms. Deletion of the constitutive first exon of Dory by CRISPR-Cas9 genome editing resulted in the impairment of spatial memory and some aspects of balance in female but not male mice. Dory-null mice presented without overt changes in brain morphology. Knockdown of the rat homolog of Dory in dorsal hippocampus using antisense oligonucleotides confirmed inhibition of spatial memory in females only. RNA sequencing and mass spectrometry revealed differential hippocampal gene and protein expression profiles, notably of prolactin, growth hormone and pro-opiomelanocortin, between male and female Dory knockout mice.