Krishnan Sudha, Intlekofer Karlie A, Aggison Leah K, Petersen Sandra L
Department of Biology, University of Massachusetts-Amherst, 611 North Pleasant Street, Amherst, MA 01003, USA.
Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16692-7. doi: 10.1073/pnas.0906293106. Epub 2009 Sep 17.
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 alpha (TNFalpha)-TNF receptor 2 (TNFR2)-NFkappaB 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 TNFalpha-dependent NFkappaB 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 TNFalpha 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.
性二态性脑核是性别特异性神经功能和疾病易感性的基础，但二态性的发育基础却知之甚少。在这些研究中，我们聚焦于腹侧室旁前核（AVPV），该核在雌性中更大，并且对促黄体生成素（LH）释放的雌性典型周期性激增模式至关重要。AVPV大小和功能的性别差异源于优先发生在发育中的雄性体内的细胞凋亡。为了确定负责AVPV性别分化的上游通路，我们使用了靶向凋亡微阵列以及体内和体外后续研究。我们发现肿瘤坏死因子α（TNFα）-肿瘤坏死因子受体2（TNFR2）-核因子κB细胞存活通路在出生后第2天（PND2）的雌性AVPV中活跃，而在雄性对应物中受到抑制。编码该通路关键成员的基因仅在γ-氨基丁酸能神经元中表达。特别是一个基因，肿瘤坏死因子受体相关因子2（TRAF2）抑制蛋白（trip），在雄性中表达更高，并且它抑制TNFα依赖的核因子κB激活和bcl-2基因表达。雄性AVPV中bax和bad mRNA水平也更高，但这两个基因均不受TNFα或TRIP的调控。最后，trip基因在视前区性二态核（SDN-POA）中不表达，在该核中细胞凋亡在雌性中高于雄性。这些发现构成了AVPV性别分化新模型的基础，该模型可能也适用于其他性二态核的发育。
