Presenting Author Duke University Durham, North Carolina
G-protein coupled receptors (GPCRs) are pivotal to neuronal functions such as neurotransmission and memory formation, and aberrant GPCR signaling has been implicated in complex neuropsychiatric disorders. Our ability to develop efficient therapeutic strategies therefore hinges on better understanding of the molecular factors that govern GPCR activity. Upon activation, GPCRs modulate a myriad of downstream second messengers and molecules that generate cellular responses, including the transcription of cAMP-dependent target genes. Through a genome-wide CRISPR-based screen with a fluorescent cAMP transcriptional reporter, we identified RNA-binding motif 12 (Rbm12) as a novel potent repressor of the GPCR/cAMP pathway. While Rbm12 is a genetic risk factor for familial psychosis, its precise cellular functions are unknown. We hypothesize that the loss of Rbm12’s regulation of the GPCR/cAMP pathway contributes to the development of psychosis. To investigate this intriguing possibility, we performed CRISPR-based gene editing to show that Rbm12 deficiency leads to increased cAMP accumulation and hyperactivation of multiple cAMP-dependent target genes downstream of several key neurotransmitter GPCRs. The signaling hyperactivation caused by Rbm12 loss is similarly conserved in human induced pluripotent stem cell-derived neurons. Furthermore, we demonstrate that disease-linked truncating mutations in Rbm12 (c.2377Ggt;T and c.2532delT) fail to rescue the signaling hyperactivation due to possible loss-of-function and protein instability, respectively. Together, these experiments provide critical insights into this uncharacterized gene. By uncovering the novel regulatory role of a neuropsychiatric disease risk gene in GPCR signaling, we expand our understanding of the molecular basis of complex neurobiological disorders and enable the identification of novel druggable targets.
National Institute of Health R35 Award to Nikoleta G. Tsvetanova and American Association of University Women International Fellowship (2021-2022) to Khairunnisa Mentari Semesta
