Homeodomain Protein Otp and Activity-Dependent Splicing Modulate Neuronal Adaptation to Stress

Abstract

SUMMARY Regulation of corticotropin-releasing hormone (CRH) activity is critical for the animal’s adaptation to stressful challenges, and its dysregulation is associated with psychiatric disorders in humans. However, the molecular mechanism underlying this transcriptional response to stress is not well understood. Using various stress paradigms in mouse and zebrafish, we show that the hypothalamic transcription factor Orthopedia modulates the expression of CRH as well as the splicing factor Ataxin 2-Binding Protein-1 (A2BP1/Rbfox-1). We further show that the G protein coupled receptor PAC1, which is a known A2BP1/Rbfox-1 splicing target and an important mediator of CRH activity, is alternatively spliced in response to a stressful challenge. The generation of PAC1-hop messenger RNA isoform by alternative splicing is required for termination of CRH transcription, normal activation of the hypothalamic-pituitary-adrenal axis and adaptive anxiety-like behavior. Our study identifies an evolutionarily conserved biochemical pathway that modulates the neuronal adaptation to stress through transcriptional activation and alternative splicing.

CD44 and OTP Are Strong Prognostic Markers for Pulmonary Carcinoids

“…Because nuclear OTP was also present in 2 limited stage SCLC cases (both CD44-negative) with good outcome, OTP might also be a prognostic indicator in highgrade neuroendocrine lung carcinomas. For OTP, an evolutionary conserved homeodomain-containing transcription factor, currently only functions within the central nervous system have been described (33)(34)(35). OTP has important roles in the development of the neurosecretory system in the hypothalamus and in terminal differentiation of neuroblasts (33,35).…”

“…Especially differentiation, proliferation, and migration of Otp-expressing cells were severely abrogated in Otp À/À mice (33). Amir-Zilberstein and colleagues (34) reported that Otp can be induced by stress, leading to transcriptional activation of, for example, corticotropin-releasing hormone. Only recently, Kim and colleagues (36) have described OTP for the first time in the context of cancer, showing OTP methylation in breast cancer using CpG microarray analysis.…”

Molecular regulation of hypothalamic development and physiological functions

“…4b). While deletion of Otp leads to embryonic lethality in mice, deletion of Otp only affects stress adaptation in the zebrafish [111]. …”

Specification of posterior hypothalamic neurons requires coordinated activities of Fezf2, Otp, Sim1a and Foxb1.2

“…The function of hypothalamic regulators seems to have been highly conserved during evolution and zebrafish orthologs have similar roles to their mouse counterparts (Machluf et al, 2011). For example, zebrafish Otp and Sim1/Arnt2 are required for the development and function of neuroendocrine cells as well as for the development of diencephalic dopaminergic (DA) neurons (Amir-Zilberstein et al, 2012;Blechman et al, 2007;Del Giacco et al, 2006;Eaton and Glasgow, 2006;Eaton and Glasgow, 2007;Eaton et al, 2008;Löhr et al, 2009;Ryu et al, 2007). Zebrafish otpb is regulated by the zinc-finger protein Fezf2 (Blechman et al, 2007), which was originally identified as a factor upregulated by overexpression of Dkk1 in zebrafish (Hashimoto et al, 2000).…”