Sex differences in the level of Bcl-2 family proteins and caspase-3 activation in the sexually dimorphic nuclei of the preoptic area in postnatal rats

Tsukahara, Shinji; Kakeyama, Masaki; Toyofuku, Yuki

doi:10.1002/neu.20276

Cited by 50 publications

(56 citation statements)

References 36 publications

(55 reference statements)

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“…It is also consistent with work of others who found higher levels of Bcl2 protein in the AVPV of developing females (10). Our in vitro data show that TNF␣ increases both NFB p65 subunits and Bcl2 gene expression in N42 cells and that TRIP inhibits both.…”

Section: Discussionsupporting

confidence: 81%

“…Previous work similarly demonstrated that Bax protein levels are higher in male AVPV, but that work found no differences in Bad protein levels (10). An important finding in our studies was that, unlike bcl2, neither bax nor bad gene expression was regulated by TNF␣ or TRIP.…”

Section: Discussionsupporting

confidence: 50%

“…Consistent with this idea, cells in the developing male AVPV express higher levels of the proapoptotic gene, bax, while expression of the prosurvival gene, bcl2, is more abundant in the developing female AVPV (10). The Bcl2/Bax ratio determines whether or not apoptosis will be triggered in the AVPV, because genetic manipulations of either Bcl2 or Bax expression alter the volume of the nucleus (11,12).…”

supporting

confidence: 56%

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Central role of TRAF-interacting protein in a new model of brain sexual differentiation

Krishnan

Intlekofer

Aggison

et al. 2009

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

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Sexually dimorphic brain nuclei underlie gender-specific neural functions and susceptibility to disease, but the developmental basis of dimorphisms is poorly understood. In these studies, we focused on the anteroventral periventricular nucleus (AVPV), a nucleus that is larger in females and critical for the female-typical cyclic surge pattern of luteinizing hormone (LH) release. Sex differences in the size and function of the AVPV result from apoptosis that occurs preferentially in the developing male. To identify upstream pathways responsible for sexual differentiation of the AVPV, we used targeted apoptosis microarrays and in vivo and in vitro follow-up studies. We found that the tumor necrosis factor ␣ (TNF␣)-TNF receptor 2 (TNFR2)؊NFB cell survival pathway is active in postnatal day 2 (PND2) female AVPV and repressed in male counterparts. Genes encoding key members of this pathway were expressed exclusively in GABAergic neurons. One gene in particular, TNF receptor-associated factor 2 (TRAF2)-inhibiting protein (trip), was higher in males and it inhibited both TNF␣-dependent NFB activation and bcl-2 gene expression. The male AVPV also had higher levels of bax and bad mRNA, but neither of these genes was regulated by either TNF␣ or TRIP. Finally, the trip gene was not expressed in the sexually dimorphic nucleus of the preoptic area (SDN-POA), a nucleus in which apoptosis is higher in females than males. These findings form the basis of a new model of sexual differentiation of the AVPV that may also apply to the development of other sexually dimorphic nuclei.NFkB ͉ TNFR2 ͉ TNF␣ ͉ sexual dimorphism ͉ apoptosis S ex differences in the morphology of brain nuclei were first observed over 30 years ago (1), but the physiological significance of these differences is known in only a few cases. The neural control of gonadotropin release in rodents is perhaps the best studied example of sex-specific physiology linked to neural dimorphisms. Females have a cyclic pattern that culminates in the preovulatory surge of luteinizing hormone (LH) release on one day of the cycle (2). This female-typical pattern of LH release is controlled by the anteroventral periventricular nucleus (AVPV) (3-6), one of the few sexually dimorphic nuclei that is larger in females. Clearly, sexual dimorphisms of the nucleus are linked to function, because developmental manipulations that alter the size of the AVPV region (7) result in inappropriate gonadotropin release patterns and infertility in adulthood (8).Sexual differentiation of the AVPV, like that of other dimorphic nuclei, is thought to be through apoptosis (9). Consistent with this idea, cells in the developing male AVPV express higher levels of the proapoptotic gene, bax, while expression of the prosurvival gene, bcl2, is more abundant in the developing female AVPV (10). The Bcl2/Bax ratio determines whether or not apoptosis will be triggered in the AVPV, because genetic manipulations of either Bcl2 or Bax expression alter the volume of the nucleus (11, 12). Unfortunately, we still have ...

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 50%

supporting

confidence: 56%

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Central role of TRAF-interacting protein in a new model of brain sexual differentiation

Krishnan

Intlekofer

Aggison

et al. 2009

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

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“…These differences may be due to a differential balance in the expression of members of the antiapoptotic family of Bcl-2 genes, and those in the pro-apoptotic family of Bax family genes. Male and female mice with mutations to these genes have significant changes in neuron numbers in the AVPV and SDN-POA, and there are natural sex differences in the expression of apoptotic genes in wildtype animals [172,53,157]. More specifically, deletion of Bax (proapoptotic) abolished sex differences in AVPV cell numbers [53], and overexpression of Bcl-2 (anti-apoptotic) had a similar effect [172].…”

Section: Mechanisms For Hormone Effects On Avpv and Sdn-poa Morphologymentioning

confidence: 99%

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

Gore¹

2008

Frontiers in Neuroendocrinology

230

122

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The ability of a species to reproduce successfully requires the careful orchestration of developmental processes during critical time points, particularly the late embryonic and early postnatal periods. This article begins with a brief presentation of the evidence for how gonadal steroid hormones exert these imprinting effects upon the morphology of sexually differentiated hypothalamic brain regions, the mechanisms underlying these effects, and their implications in adulthood. Then, I review the evidence that aberrant exposure to hormonally-active substances such as exogenous endocrine-disrupting chemicals (EDCs), may result in improper hypothalamic programming, thereby decreasing reproductive success in adulthood. The field of endocrine disruption has shed new light on the discipline of basic reproductive neuroendocrinology through studies on how early life exposures to EDCs may alter gene expression via non-genomic, epigenetic mechanisms, including DNA methylation and histone acetylation. Importantly, these effects may be transmitted to future generations if the germline is affected via transgenerational, epigenetic actions. By understanding the mechanisms by which natural hormones and xenobiotics affect reproductive neuroendocrine systems, we will gain a better understanding of normal developmental processes, as well as to develop the potential ability to intervene when development is disrupted.

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“…Supporting this hypothesis are the studies demonstrating dimorphism in the expression of pro-and anti-apoptotic proteins, Bax and Bcl-2, respectively, in structurally dimorphic brain regions [85,86]. Moreover, both overexpression of anti-apoptotic proteins or deletion of pro-apoptotic genes in brain have been shown to eliminate structural sex differences [87,88].…”

Section: Same Histone Modifications Results In Sexually Dimorphic Braimentioning

confidence: 91%

Histone modifications proposed to regulate sexual differentiation of brain and behavior

2010

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Expression of sexually dimorphic behaviors critical for reproduction depends on the organizational actions of steroid hormones on the developing brain. We offer the new hypothesis that transcriptional activities in brain regions executing these sexually dimorphic behaviors are modulated by estrogeninduced modifications of histone proteins. Specifically, in preoptic nerve cells responsible for facilitating male sexual behavior in rodents, gene expression is fostered by increased histone acetylation and reduced methylation (Me), and, that the opposite set of histone modifications will be found in females. Conversely, in ventromedial hypothalamic neurons that are responsible for coordinating female sexual behavior, transcriptional activities in genetic females are fostered by increased histone acetylation and reduced Me, and, further, that the opposite set of histone modifications will be found in males. Thus, these epigenetic events will guarantee that effects of sex hormone exposure during the neonatal critical period will be translated into lasting sex differences in adult reproductive behaviors.

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Sex differences in the level of Bcl-2 family proteins and caspase-3 activation in the sexually dimorphic nuclei of the preoptic area in postnatal rats

Cited by 50 publications

References 36 publications

Central role of TRAF-interacting protein in a new model of brain sexual differentiation

Central role of TRAF-interacting protein in a new model of brain sexual differentiation

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

Histone modifications proposed to regulate sexual differentiation of brain and behavior

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