Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2

Matsumoto, S.; Yamazaki, C.; Masumoto, Kouji; Nagano, Mamoru; Naito, Masanori; Soga, Tsunehiko; Hiyama, Hideki; Matsumoto, Mitsuyuki; Takasaki, Jun; Kamohara, Masazumi; Matsuo, Ayako; Ishii, Hiroyuki; Kobori, Masato; Katoh, Miyuki; Matsushime, Hitoshi; Furuichi, Kiyoshi; Shigeyoshi, Yasufumi

doi:10.1073/pnas.0508881103

Cited by 255 publications

(275 citation statements)

References 52 publications

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“…exhibited normal patterns of feeding, grooming, and nesting behavior. Consistent with the reported sterility of a different Prokr2 null mutation (15), male and female m/m mice failed to breed.…”

Section: Resultssupporting

confidence: 67%

“…Functional inactivation of the Prokr2 gene was confirmed by radioligand binding of mamba intestinal toxin 1 (MIT), a peptidergic homolog of endocrine gland-derived VEGF, which binds to both Prokr2 and Prokr1 receptors (13). The latter, however, is expressed at very low levels in the rodent brain, and so the binding we observed in wild-type mouse brain likely represented Prokr2 (14,15). In confirmation, the distribution of 125 I-MIT-binding sites overlapped that of Prokr2 mRNA as described in refs.…”

Section: Resultsmentioning

confidence: 91%

“…Loss of Prok2/Prokr2 disrupts olfactory bulb development and leads to infertility (15,24,26). Disturbed circadian behavior may, therefore, be related indirectly to altered olfactory cues and/or infertility.…”

Section: Discussionmentioning

confidence: 99%

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Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei

Prosser

Bradley

Chesham

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

136

138

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The suprachiasmatic nucleus (SCN), the brain's principal circadian pacemaker, coordinates adaptive daily cycles of behavior and physiology, including the rhythm of sleep and wakefulness. The cellular mechanism sustaining SCN circadian timing is well characterized, but the neurochemical pathways by which SCN neurons coordinate circadian behaviors remain unknown. SCN transplant studies suggest a role for (unidentified) secreted factors, and one potential candidate is the SCN neuropeptide prokineticin 2 (Prok2). Prok2 and its cognate prokineticin receptor 2 (Prokr2/Gpcr73l1) are widely expressed in both the SCN and its neural targets, and Prok2 is light-regulated. Hence, they may contribute to cellular timing within the SCN, entrainment of the clock, and/or they may mediate circadian output. We show that a targeted null mutation of Prokr2 disrupts circadian coordination of the activity cycle and thermoregulation. Specifically, mice lacking Prokr2 lost precision in timing the onset of nocturnal locomotor activity; and under both a light/dark cycle and continuous darkness, there was a pronounced temporal redistribution of activity away from early to late circadian night. Moreover, the coherence of circadian behavior was significantly reduced, and nocturnal body temperature was depressed. Entrainment by light is not, however, dependent on Prokr2, and bioluminescence real-time imaging of organotypical SCN slices showed that the mutant SCN is fully competent as a circadian oscillator. We conclude that Prokr2 is not necessary for SCN cellular timekeeping or entrainment, but it is an essential link for coordination of circadian behavior and physiology by the SCN, especially in defining the onset and maintenance of circadian night.T he suprachiasmatic nucleus (SCN) of the hypothalamus constitutes an autonomous circadian pacemaker necessary for the maintenance of daily rhythms, including the cycle of sleep and wakefulness (1). The molecular basis of the cellular oscillator of the SCN is broadly characterized, but how the SCN signals circadian time to other sites in the brain and thence to peripheral tissues is unclear (2). Neuroanatomical projections from the SCN run predominantly to local hypothalamic and thalamic structures (3), including the dorsomedial nucleus (DMN), a principal site for the regulation of sleep and wakefulness and circadian arousal by behavioral cues (4, 5). How such ''hard-wired'' connections influence SCN targets remains open to question. Although electrical signaling by means of synaptic contacts is likely important (6), encapsulated SCN grafts unable to form synaptic contacts with host tissues are nevertheless able to establish circadian activity/rest cycles in previously arrhythmic, SCN-lesioned recipients (7). This finding indicates that paracrine factors from the SCN mediate circadian coordination within the brain. A small number of candidate factors have been explored, including TGF-␣ (8) and cardiotrophin-like cytokine (9). These factors are expressed by the SCN on a circadian basis, and local ...

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Section: Resultssupporting

confidence: 67%

Section: Resultsmentioning

confidence: 91%

See 1 more Smart Citation

Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei

Prosser

Bradley

Chesham

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

136

138

View full text Add to dashboard Cite

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“…In Prokr2 or Prok2 homozygous knockout mice, and mice carrying Fgfr1 or Fgf8 hypomorphic mutations in the homozygous state, however, the migration of these cells is disrupted too. 14,65,79,80 The mechanism of the putative defect of GnRH cell migration in KS is still conjectural. It could be either a consequence of the early degeneration of olfactory nerve and terminal nerve axons, which act as guiding cues, or a process directly affecting the GnRH cells themselves.…”

Section: Pathophysiologymentioning

confidence: 99%

Kallmann syndrome

2008

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The Kallmann syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked recessive form of the disease. Mutations in FGFR1 or FGF8, encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance. Finally, mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic/oligogenic KS transmission modes. Notably, mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered.

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“…Notably, the two biallelic mutations were also detected in the heterozygous state in other unrelated patients. The large excess of heterozygous patients for PROKR2 mutations versus homozygotes and compound heterozygotes, combined with the observation that only homozygous knockout mice reproduce the KS phenotype, 13 led us to consider the possibility of a digenic or oligogenic mode of transmission of the human disease, especially in heterozygous patients. Although PROK2 was an obvious candidate, we did not find a mutation of this gene in any of the patients carrying a mutated PROKR2 allele.…”

Section: Introductionmentioning

confidence: 99%

Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome

et al. 2008

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Kallmann syndrome is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Putative loss-of-function mutations in PROKR2 or PROK2, encoding prokineticin receptor-2 (a G protein-coupled receptor), and one of its ligands, prokineticin-2, respectively, have recently been reported in approximately 10% of Kallmann syndrome affected individuals. Notably, given PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state in patients, thus raising the question of a possible digenic inheritance of the disease in heterozygous patients. Indeed, one of these patients was also carrying a missense mutation in KAL1, the gene responsible for the X chromosome-linked form of Kallmann syndrome. Mutations in PROK2, however, have so far been found only in the heterozygous state. Here, we report on the identification of PROK2 biallelic mutations, that is, a missense mutation, p.R73C, and a frameshift mutation, c.163delA, in two out of 273 patients presenting as sporadic cases. We conclude that PROK2 mutations in the homozygous state account for a few cases of Kallmann syndrome. Moreover, since the same R73C mutation was previously reported in the heterozygous state, and because Prok2 knockout mice exhibit an abnormal phenotype only in the homozygous condition, we predict that patients carrying monoallelic mutations in PROK2 have another disease-causing mutation, presumably in still undiscovered Kallmann syndrome genes.

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Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2

Cited by 255 publications

References 52 publications

Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei

Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei

Kallmann syndrome

Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome

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