Review
Sexual differentiation of the gonadotropin surge release mechanism: A new role for the canonical NfκB signaling pathway

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Abstract

Sex differences in luteinizing hormone (LH) release patterns are controlled by the hypothalamus, established during the perinatal period and required for fertility. Female mammals exhibit a cyclic surge pattern of LH release, while males show a tonic release pattern. In rodents, the LH surge pattern is dictated by the anteroventral periventricular nucleus (AVPV), an estrogen receptor-rich structure that is larger and more cell-dense in females. Sex differences result from mitochondrial cell death triggered in perinatal males by estradiol derived from aromatization of testosterone. Herein we provide an historical perspective and an update describing evidence that molecules important for cell survival and cell death in the immune system also control these processes in the developing AVPV. We conclude with a new model proposing that development of the female AVPV requires constitutive activation of the Tnfα, Tnf receptor 2, NfκB and Bcl2 pathway that is blocked by induction of Tnf receptor-associated factor 2-inhibiting protein (Traip) in the male.

Graphical abstract

Hypothesized role of the Tnfα–TnfR2–NfκB pathway in E2 control of sexual differentiation of the anteroventral periventricular (AVPV) nucleus.

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Highlights

► Sex-specific patterns of luteinizing hormone are critical for gonadal functions. ► The anteroventral periventricular (AVPV) nucleus dictates LH release patterns in rodents. ► The AVPV is smaller in males due to developmental cell death. ► Cell death is triggered by Traip repression of NfκB activation and Bcl2 induction.

Introduction

Sex-specific patterns of luteinizing hormone (LH) release are fundamental to reproduction in mammals. The male pattern is tonic, while the female pattern is cyclic and culminates in a preovulatory surge of LH release. These patterns are controlled by sexually dimorphic neural structures that differentiate perinatally when the testes, but not the ovaries are actively secreting steroid hormones [9]. Mimicking the male hormonal profile in perinatal females leads to a condition characterized by polycystic ovaries and infertility [6], [7]. Therefore, to better understand the etiology of polycystic ovarian syndrome and other types of hypothalamic infertility, it is important to determine the mechanisms underlying the process of sexual differentiation of the brain.

In the first section of this paper, we review the pioneering research on sexual differentiation of the neural substrate that controls gonadotropin release. In the second section, we describe research that identified the anteroventral periventricular nucleus (AVPV) as a region critical for the female pattern of cyclic LH release in rodents. The third section focuses on phenotypic characterization of neurons that comprise the AVPV. The fourth section discusses work showing that male-specific apoptosis plays a key role in sexual differentiation of the AVPV. The fifth section provides evidence that a novel protein, tumor necrosis factor receptor associated factor 2-inhibiting protein (Traip), induces apoptosis in the male AVPV by blocking nuclear factor κB (NfκB) activation. In the final section, we present a new model of AVPV sexual differentiation and describe future directions for this research.

Section snippets

Sexual differentiation of gonadotropin release patterns: Pioneers of the early frontier

Normal ovarian and testicular functions depend on sex-specific gonadotropin release patterns to such an extent that alterations in these patterns reduce fertility. Sex differences in the mammalian pituitary gonadotropin content were first observed in the early 1900s [21], [33], [35], [94], [149]. In 1933 Fevold et al. [37] showed that the pituitary produced two gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH), and that cyclic changes in the release of these

Localization of sexually differentiated brain nuclei important for ovulation

In the 1980s, research by a number of laboratories focused on more precisely defining the region of the POA required for cyclic LH surge release. Studies of Wiegand and Terasawa showed that small lesions of the medial preoptic nucleus (MPN) produced persistent estrus in rats [146]. In addition, only lesions in this region blocked LH surge release induced by E2 and progesterone (P4) in ovariectomized (OVX) rats. Work by Ronnekleiv and Kelly showed that MPN lesions caused accumulation of

Phenotypic identification of sexually dimorphic neuronal populations in the AVPV

A group of DA neurons was the first population of AVPV cells shown to be sexually dimorphic [130]. Consistent with its larger volume [11], [28], the female AVPV contains a greater density of DA fibers and more numerous cell bodies [130]. In addition, perinatal treatment of females with testosterone (T) decreases the number of AVPV DA neurons [131]. Although these neurons may be important for sex-specific AVPV functions, it seems unlikely that they are directly responsible for T-induced

The role of cell death in AVPV sexual differentiation

After more than 50 years of study, the mechanisms through which perinatal T exposure initiates AVPV masculinization are not completely understood; however, it is clear that the process involves aromatization of T to E2 [89], [90], [91] and culminates in cell death (recently reviewed in [40], [141]). The first evidence for this concept came from work of Murakami and Arai showing that neonatal T exposure increases the number of pyknotic nuclei in the developing AVPV [101]. Later the same group

Upstream regulators of mitochondrial cell death in the AVPV

Mitochondrial apoptosis is clearly important for sexual differentiation of the AVPV [40], [141], but there is little information about the upstream regulators of this pathway. To address this issue, we used targeted apoptosis microarrays to identify genes differentially expressed in PND2 male and female AVPV. Surprisingly, more than half of the identified genes were linked to tumor necrosis factor α (Tnfα) signaling [76]. Tnfα is a cytokine that regulates diverse developmental functions

Conclusions: Towards a new model of AVPV sexual differentiation

Recent findings described above suggest that a constitutively active Tnfα–Tnfr2–NfκB–Bcl2 pathway is important for cell survival in the developing AVPV, and that Traip blocks this pathway [76]. Although Traip-dependent downregulation of Bcl2 is undoubtedly important for apoptosis in the male AVPV, the pro-apoptotic protein, Bax, also plays a role in sexual differentiation of this nucleus [41]. This protein is higher in the developing AVPV of males, but does not appear to be regulated by Traip

Acknowledgment

Funding was provided by NIH Grants HD27305 and ES013885 to S.L.P.

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