Zebrafish orthopedia (otp) is required for isotocin cell development

Abstract

Several behavioral and physiological processes such as social, sexual, and maternal behaviors, learning and memory, and parturition are influenced by the neurohypophysial peptide oxytocin. Studies in knockout mice have identified four transcriptional regulatory genes that are required for oxytocin neuronal development in the hypothalamus. These are the basic helix-loop-helix PAS genes Single-minded 1 (Sim1) and Arylhydrocarbon receptor nuclear translocator 2 (Arnt2), the POU homeobox gene Pou3f2, and the paired homeobox gene Orthopedia (Otp). Overall, however, the molecular control of oxytocin cell development is poorly understood. Studies in zebrafish provide a complementary view to mouse knockout experiments and facilitate understanding of neuroendocrine cell development. Isotocin, which is orthologous to oxytocin, is expressed early in the developing zebrafish brain. In this paper we show that zebrafish otp mRNA expression in the embryonic forebrain is dynamic and complex, and that it overlaps with isotocin expression in the dorsal preoptic area. Additionally, these studies demonstrate that otp is required for isotocin cell development. Evidence is also provided that otp and sim1 function in parallel to direct the differentiation of isotocin cells, and that otp is unlikely to affect brain patterning. Overall, these studies support the hypothesis that the role of otp in zebrafish neuroendocrine cell development is evolutionarily conserved with that of mammals.

Zebrafish diencephalic A11-related dopaminergic neurons share a conserved transcriptional network with neuroendocrine cell lineages

“…Not all the neurons in the PO depend on Arnt2/Sim1 function, as only one of two SST-expressing groups in the PO is reduced and DA neurons form normally in the PO. Combined with a recent study, which shows the requirement of Sim1 for ITNP-and VSNP-producing cells in the PO (Eaton and Glasgow, 2006;Eaton and Glasgow, 2007), our data establish that the specification of specific neurosecretory cell types of the hypothalamus is largely conserved in zebrafish. The mammalian Otp and Arnt2/Sim1 pathways eventually merge at the level of Pou3f2/Brn2.…”

“…4D-F). A requirement for sim1 in specification of zebrafish itnp-and vsnp-expressing neurons has already been suggested (Eaton and Glasgow, 2006;Eaton and Glasgow, 2007). In arnt2 m1055 mutants, as in sim1a morphants, itnp and vsnp neurons in the preoptic region were strongly reduced or absent (Fig.…”

“…Otp is essential for specification of crh-, sst-and isotocin-(itnp; the zebrafish ortholog of mammalian OT) expressing cells in the preoptic region of the hypothalamus (PO) (Blechman et al, 2007;Ryu et al, 2007). Knockdown of zebrafish sim1 leads to reduction or loss of itnp-and vasotocin-(vsnp; the zebrafish ortholog of mammalian VP) expressing cells in the zebrafish preoptic region (Eaton and Glasgow, 2007;Eaton et al, 2008). Thus, Otp and Sim1 appear to be involved in specification of various neuronal subtypes in the zebrafish diencephalon.…”

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).…”

Sim1a and Arnt2 contribute to hypothalamo-spinal axon guidance by regulating Robo2 activity via a Robo3-dependent mechanism

“…The homeodomain transcription factor Orthopedia (Otp) is co-expressed with the two PAS domain factors Sim1 and Arnt2, the latter two forming functional heterodimers. Otp/Sim1/Arnt2-dependent cell lineages in mammals (Acampora et al, 1999;Michaud et al, 2000;Michaud et al, 1998;Wang and Lufkin, 2000) and zebrafish (Blechman et al, 2007;Del Giacco et al, 2006;Eaton and Glasgow, 2006;Eaton and Glasgow, 2007;Löhr et al, 2009;Ryu et al, 2007) include neuroendocrine cells characterised by expression of the peptide hormones corticotropin-releasing hormone, thyrotropin-releasing hormone, arginine vasopressin, oxytocin and somatostatin. In addition to neuroendocrine lineages, Otp/Sim1/Arnt2 have been shown to control development of hypothalamic A11-type dopaminergic (DA) neurons in zebrafish and, for Otp, mammals (Borodovsky et al, 2009;Löhr et al, 2009;Ryu et al, 2007).…”