Abnormal development of the locus coeruleus in Ear2(Nr2f6)-deficient mice impairs the functionality of the forebrain clock and affects nociception

Abstract

The orphan nuclear receptor Ear2 (Nr2f6) is transiently expressed in the rostral part of the rhombic lip in which the locus coeruleus (LC) arises. LC development, regulated by a signaling cascade (Mash1 → Phox2b → Phox2a), is disrupted in Ear2 −/− embryos as revealed by an approximately threefold reduction in the number of Phox2a-and Phox2b-expressing LC progenitor cells. Mash1 expression in the rhombic lip, however, is unaffected, placing Ear2 in between Mash1 and Phox2a/b. Dopamine-␤-hydroxylase and tyrosine hydroxylase staining demonstrate that >70% of LC neurons are absent in the adult with agenesis affecting primarily the dorsal division of the LC. Normally, this division projects noradrenergic efferents to the cortex that appear to be diminished in Ear2 −/− since the cortical concentration of noradrenaline is four times lower in these mice. The rostral region of the cortex is known to contain a circadian pacemaker regulating adaptability to light-and restricted food-driven entrainment. In situ hybridization establishes that the circadian expression pattern of the clock gene Period1 is abolished in the Ear2 −/− forebrain. Behavioral experiments reveal that Ear2 mutants have a delayed entrainment to shifted light-dark cycles and adapt less efficiently to daytime feeding schedules. We propose that neurons in the dorsal division of LC contribute to the regulation of the forebrain clock, at least in part, through targeted release of noradrenaline into the cortical area.[Keywords: Circadian rhythm; Ear2; forebrain clock; locus coeruleus; nociception; nuclear orphan receptor] Supplemental material is available at http://www.genesdev.org.

Orphan Nuclear Receptor Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) Protein Negatively Regulates Bone Morphogenetic Protein 2-induced Osteoblast Differentiation through Suppressing Runt-related Gene 2 (Runx2) Activity

“…COUP-TFs are widely expressed during embryonic development and have been shown to regulate many key biological processes, including angiogenesis, organogenesis, adipogenesis, neurogenesis, cell fate determination, and metabolic homeostasis (7)(8)(9)(10)(11)(12). Among the three mammalian orthologs of COUP-TFs including COUP-TFI, COUP-TFII, and EAR2, COUP-TFII can act as either a positive or negative regulator of transcription.…”

“Feeding time” for the brain: A matter of clocks

“…Starting with the observation that Per gene expression is dampened in the frontal cortex of Ear2À/À mice, it was hypothesized that these mice have a defective circadian timing system in the forebrain. When Ear2À/À mice are challenged with restricted feeding, FAA is significantly reduced, concomitant with a drastic reduction of noradrenaline concentration in the frontal cortex (Warnecke et al, 2005 may not be the unique transmitter: neurons in the locus coeruleus also express neuropeptides such as vasopressin, galanin and neuropeptide Y, which may be responsible for the observed reduction in frontal cortex rhythmicity and indirectly related to reduced FAA. Moreover no expression of known clock genes could be detected in the locus coeruleus (Warnecke et al, 2005), which would indicate that this structure does not harbour its own clock but constitutes a relay conveying information to the forebrain, possibly from or to the FEC.…”

“…When Ear2À/À mice are challenged with restricted feeding, FAA is significantly reduced, concomitant with a drastic reduction of noradrenaline concentration in the frontal cortex (Warnecke et al, 2005 may not be the unique transmitter: neurons in the locus coeruleus also express neuropeptides such as vasopressin, galanin and neuropeptide Y, which may be responsible for the observed reduction in frontal cortex rhythmicity and indirectly related to reduced FAA. Moreover no expression of known clock genes could be detected in the locus coeruleus (Warnecke et al, 2005), which would indicate that this structure does not harbour its own clock but constitutes a relay conveying information to the forebrain, possibly from or to the FEC. If this were the case, functional impairment of the locus coeruleus could lead to only partial delivery of inputs to the FEC or incomplete output signals to its effectors, thus resulting in reduction of FAA.…”

“…Ear2 can homo-or hetero-dimerize with COUP-TFI and COUP-TFII (Avram et al, 1999) and bind to enhancers in the sequence of various genes. Ear2À/À mice lack the major part of the locus coeruleus, which provides the majority of noradrenergic transmission in mammals (Warnecke et al, 2005) and contacts a great number of brain structures, particularly in the forebrain. Starting with the observation that Per gene expression is dampened in the frontal cortex of Ear2À/À mice, it was hypothesized that these mice have a defective circadian timing system in the forebrain.…”

Ligand-gated Ion Channels

“…(Raghuram et al, 2007;Yin et al, 2007) A synthetic agonist, GSK4112, has been described (Grant et al, 2010) Rev-erbb NR1D2 EAR1b, RVR, BD73 ENSG00000174738 Haem (Raghuram et al, 2007;Yin et al, 2007) A synthetic agonist, GSK4112, has been described (Grant et al, 2010) (Young et al, 1998); gene disruption appears without effect on testicular development or function (Shyr et al, 2002)) TLX NR2E1 Tailless homolog, TLL ENSG00000112333 Gene disruption is associated with abnormal brain development (Monaghan et al, 1997;Land and Monaghan, 2003) PNR NR2E3 Photoreceptor-specific nuclear receptor, retina-specific nuclear receptor ENSG00000031544 -COUP-TFI NR2F1 COUPa, EAR3, SVP44 ENSG00000175745 Gene disruption is perinatally lethal (Qiu et al, 1997) COUP-TFII NR2F2 COUPb, ARP1, SVP40 ENSG00000185551 Gene disruption is embryonically lethal (Pereira et al, 1999) EAR2 NR2F6 V-erb-related gene ENSG00000160113 Gene disruption impairs CNS development (Warnecke et al, 2005) (Suetsugi et al, 2003); activated by the synthetic agonist GSK4716 (Zuercher et al, 2005) and blocked by XCT790 (Willy et al, 2004) ERRb NR3B2 ESRL2, estrogen-related receptor b, estrogen receptor-like 2…”