Temperature-Sensitive Phenotype in Mice Lacking Pituitary Adenylate Cyclase-Activating Polypeptide

Gray, Sarah L.; Yamaguchi, Nobuharu; Vencová, Petra; Sherwood, Nancy M.

doi:10.1210/en.2002-220401

Cited by 131 publications

(114 citation statements)

References 48 publications

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“…PACAP peptide, when administered to mice via the third ventricle, leads to a sharp reduction of food intake (Mizuno et al, 1998). Additionally, PACAP knock-out mice exhibit severe metabolic disorders, including impairments to thermogenesis and the counterregulatory response to hypoglycemia (Gray et al, 2001(Gray et al, , 2002. The VMH has been shown to play a role in both of these processes, suggesting that PACAP may contribute to some portion of these VMH functions (Perkins et al, 1981;Borg et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Use of Laser-Capture Microdissection for the Identification of Marker Genes for the Ventromedial Hypothalamic Nucleus

Stallings²,

et al. 2005

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The ventromedial hypothalamic nucleus (VMH) plays an important role in the control of feeding and energy homeostasis. In contrast to other hypothalamic nuclei that are also known to regulate energy balance, there is a paucity of nucleus-specific marker genes for the VMH, limiting the application of molecular approaches for analyzing VMH information processing, function, and circuitry. Here, we report the use of laser-capture microdissection to isolate a set of cDNAs that are enriched in the VMH relative to two adjacent hypothalamic nuclei, the arcuate and dorsomedial hypothalamus. The relative expression levels of nine of the 12 most robustly expressed VMH-enriched genes were confirmed by real-time PCR analysis using separate RNAs from these three nuclei. Three of these VMH-enriched genes were further characterized by in situ hybridization histochemistry, including pituitary adenylate cyclase activating polypeptide, cerebellin 1, and an expressed sequence tag named LBH2. Finally, to test whether some of these genes were coordinately regulated, we monitored their expression in steroidogenic factor 1 (SF-1) knock-out mice. SF-1 is a transcription factor that controls the development of the VMH. The RNA levels for four of these genes were reduced in these knock-out animals, further suggesting that they are direct or indirect targets of this orphan nuclear receptor. The VMH-enriched genes identified here provide a basis for a functional analysis of VMH neuronal subpopulations via the use of bacterial artificial chromosome transgenics and related technologies. These results also demonstrate the utility of laser-capture microdissection coupled with microarray technology to identify nucleus-specific transcriptional networks.

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Section: Discussionmentioning

confidence: 99%

Use of Laser-Capture Microdissection for the Identification of Marker Genes for the Ventromedial Hypothalamic Nucleus

Stallings²,

et al. 2005

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“…In addition, it has been shown that PACAP Ϫ/Ϫ mice present numerous phenotypes, including high mortality of PACAP Ϫ/Ϫ mice (37), inadequate heat production (38), reduction in glucose levels (39), and deficits in circadian light response (40). It is possible that these factors could influence testicular aging as well.…”

Section: Discussionmentioning

confidence: 99%

Delayed testicular aging in pituitary adenylate cyclase-activating peptide (PACAP) null mice

Lacombe¹,

Lelièvre

Roselli

et al. 2006

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

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Age-related decline in male sex hormones is a direct consequence of testicular aging. These changes in the hormonal complement cause physiological disturbances affecting the quality of life for millions of aging men. To assess the influence on testicular aging of pituitary adenylate cyclase-activating peptide (PACAP), a polypeptide that regulates testicular steroidogenesis in vitro, we compared the testicular structure and function between C57BL͞6 wild-type and PACAP ؊/؊ male mice, at 4 and 15 months of age. We show that, in 4-month-old PACAP ؊/؊ mice, steroidogenesis (evaluated by levels of testosterone, steroidogenic acute regulatory protein, 3␤-hydroxysteroid dehydrogenase, and P450c17) was impaired. However, the testicular structure of these animals was not affected. At 15 months of age, wild-type testis displayed typical signs of aging (patchy seminiferous tubules, germ cell depletion, and vacuolization), whereas testicular structure was remarkably well conserved in PACAP ؊/؊ animals. The depletion of germ cells found in wild-type animals was associated with a higher content of peroxynitrites, a marker of reactive oxygen species, and a higher number of apoptotic cells compared with PACAP ؊/؊ mice. Our results show that testicular aging is delayed in PACAP ؊/؊ animals. Because the expression levels of steroidogenic factors are low and constant over time in knockout animals, a proposed mechanism for the protection against testicular degeneration is that production of reactive oxygen species, a byproduct of steroidogenesis that induces apoptosis, is down-regulated in PACAP ؊/؊ animals.Leydig cells ͉ reactive oxygen species ͉ steroidogenesis ͉ neuropeptide ͉ andropause

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“…In fact, most of the phenotypes reported so far in PACAP-or PAC1-deficient mice have been observed under paraphysiological conditions, such as metabolic stress after insulin injection [10,11] thermoregulatory stress [7] and septic shock following LPS injection [13]. These observations suggest that PACAP mainly acts as an emergency response factor to reinforce and sustain normal homeostatic mechanisms during prolonged periods of challenge to them.…”

Section: Discussionmentioning

confidence: 99%

Endogenous PACAP acts as a stress response peptide to protect cerebellar neurons from ethanol or oxidative insult

et al. 2005

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The rodent cerebellum is richly supplied with PACAPergic innervation. Exogenous pituitary adenylate cyclase-activating polypeptide (PACAP) increases cerebellar granule cell survival and differentiation in culture, and enhances the number of neuroblasts in the molecular and internal granule cell layers (IGL) when injected postnatally into the cerebellum in vivo. Here, we have investigated the role of endogenous PACAP during cerebellar development by comparing the morphology of normal and PACAP-deficient mouse cerebellum, and the response of cerebellar granule cells from normal and PACAP-deficient mice subjected to neurotoxic insult in culture. There was no difference in cerebellar volume or granule cell number, in 11-day-old wild type versus PACAP-deficient mice. Cultured cerebellar neurons from PACAP-deficient and wild type mice also showed no apparent differences in survival and differentiation either under depolarizing conditions, or non-depolarizing conditions in the presence or absence of either dibutyryl cAMP or 100 nM PACAP. However, cultured cerebellar neurons from PACAP-deficient mice were significantly more sensitive than wild type neurons to ethanol-or hydrogen peroxide-induced toxicity. Differential ethanol toxicity was reversed by addition of 100 nM exogenous PACAP, suggesting that endogenous PACAP has neuroprotective activity in the context of cellular insult or stress. The neuroprotective action of PACAP was mimicked by dibutryl cAMP, indicating that it occurred via activation of adenylate cyclase. These results indicate that PACAP might act to protect the brain from paraphysiological insult, including exposure to toxins or hypoxia.

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Temperature-Sensitive Phenotype in Mice Lacking Pituitary Adenylate Cyclase-Activating Polypeptide

Cited by 131 publications

References 48 publications

Use of Laser-Capture Microdissection for the Identification of Marker Genes for the Ventromedial Hypothalamic Nucleus

Use of Laser-Capture Microdissection for the Identification of Marker Genes for the Ventromedial Hypothalamic Nucleus

Delayed testicular aging in pituitary adenylate cyclase-activating peptide (PACAP) null mice

Endogenous PACAP acts as a stress response peptide to protect cerebellar neurons from ethanol or oxidative insult

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