Deletion of the<i>Ttf1</i>Gene in Differentiated Neurons Disrupts Female Reproduction without Impairing Basal Ganglia Function

Mastronardi, Claudio A.; Smiley, Gregory; Raber, Jacob; Kusakabe, Takashi; Kawaguchi, Akio; Matagne, Valérie; Dietzel, Anja; Heger, Sabine; Mungenast, Alison E.; Cabrera, Ricardo; Kimura, Shioko; Ojeda, Sergio R.

doi:10.1523/jneurosci.4238-06.2006

Cited by 68 publications

(90 citation statements)

References 75 publications

(105 reference statements)

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“…Further computational analysis of experimentally defined transcription factor binding sites (using the TransFac database) revealed that the TRG network is a subnetwork linked via cis-regulatory interactions with two non-TRGs, previously shown to play a role in the neuroendocrine control of female puberty, OCT2 (78) and TTF1 (33). This association brings up the issue of how relevant a cis-regulatory TRG network is to the overall neuroendocrine control of the pubertal process.…”

Section: Discussionmentioning

confidence: 98%

“…Although not formally tested here, the results of studies dealing with two main hubs connecting the TRG with a non-TRG regulatory network are consistent with this prediction. Male mice carrying a targeted deletion of the Cutlike1 gene are infertile (41), and female mice subjected to conditional, Cre/loxP-mediated deletion of the Ttf1 gene from neurons (33) reproductive life span by a mechanism involving loss of transcriptional control of at least one subordinate TRG (KiSS1).…”

Section: Discussionmentioning

confidence: 99%

“…to well-established criteria (32) and based on the prevailing plasma LH levels (33). The CTX was used as a control tissue.…”

Section: Trg Expression Increases In the Nonhuman Primate Hypothalamumentioning

confidence: 99%

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Expression of a Tumor-Related Gene Network Increases in the Mammalian Hypothalamus at the Time of Female Puberty

et al. 2007

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Much has been learned in recent years about the central mechanisms controlling the initiation of mammalian puberty. It is now clear that this process requires the interactive participation of several genes. Using a combination of high throughput, molecular, and bioinformatics strategies, in combination with a system biology approach, we singled out from the hypothalamus of nonhuman primates and rats a group of related genes whose expression increases at the time of female puberty. Although these genes [henceforth termed tumorrelated genes ( D URING THE LAST few years, significant progress has been made toward elucidating the basic cellular and molecular mechanisms underlying the neuroendocrine control of mammalian puberty. Specific transsynaptic and gliato-neuron communication pathways affecting the GnRH neuronal network have been identified, and the relative importance of each of these pathways in controlling the pubertal process has been demonstrated, along with some of their structural and functional interactions. The neuronal networks most critically involved in controlling GnRH release during sexual development have been shown to be those that use excitatory/inhibitory amino acids (reviewed in Ref. 1), and the recently identified neuropeptide metastin/ kisspeptin (2, 3), for neurotransmission. Cell-cell signaling molecules that, produced in astroglial cells, facilitate GnRH secretion have been identified, and genetic approaches have been used to define the physiological contribution of these molecules to the pubertal process (reviewed in Ref. 4).These efforts have also made clear that no isolated pathway or cellular subset is responsible for the neuroendocrine control of puberty. Instead, this control is likely exerted by complex regulatory gene networks composed of functional modules. A global approach for the system-level identification of such networks has never been attempted, essentially due to the lack of appropriate technology and the relative paucity of genetic and biochemical details that can be assimilated into a testable biological model. The emergence of high-throughput approaches and computational methods to organize, display, and analyze the plethora of results derived from such approaches is rapidly changing this landscape and giving us for the first time the opportunity of identifying functional genetic modules involved in the hierarchical control of puberty.Although mathematical models for common mechanisms of gene regulation are available (see, for instance, Ref. 5), most current models of genetic network architecture derive from nonmammalian species in which single metabolic or developmental pathways have been analyzed (e.g. Refs. 6 -8). The development of similar models to explain integrated functions of much more complex tissues, such as the hypothalamus, has been (and continues to be) exceedingly difficult because of the cellular heterogeneity of the nervous tissue, the lack of adequate sets of biochemical and genetic markers that can be used to build the network, the complexity of the...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Expression of a Tumor-Related Gene Network Increases in the Mammalian Hypothalamus at the Time of Female Puberty

et al. 2007

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“…[20][21][22][23] An example is the homeodomain gene TTF1, a transcription factor that was recently shown to be involved in the neuroendocrine control of both primate and rodent puberty. 24 In addition, recent findings suggest that structural remodeling of GnRH neurons may play a key role in the onset of puberty. 25 Although the initiating trigger(s) for pubertal onset is unknown for rodents, nonhuman primates and humans, earlier molecular markers have been identified, such as the newly described kisspeptin-GPR54 regulatory system.…”

Section: Figurementioning

confidence: 99%

Environmental Factors and Puberty Timing: Expert Panel Research Needs

et al. 2008

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Serono Symposia International convened an expert panel to review the impact of environmental influences on the regulation of pubertal onset and progression while identifying critical data gaps and future research priorities. An expert panel reviewed the literature on endocrine-disrupting chemicals, body size, and puberty. The panel concluded that available experimental animal and human data support a possible role of endocrine-disrupting chemicals and body size in relation to alterations in pubertal onset and progression in boys and girls. Critical data gaps prioritized for future research initiatives include (1) etiologic research that focus on environmentally relevant levels of endocrine-disrupting chemicals and body size in relation to normal puberty as well as its variants, (2) exposure assessment of relevant endocrine-disrupting chemicals during critical windows of human development, and (3) basic research to identify the primary signal(s) for the onset of gonadotropinreleasing hormone-dependent/central puberty and gonadotropin-releasing hormone-independent/peripheral puberty. Prospective studies of couples who are planning pregnancies or pregnant women are needed to capture the continuum of exposures at critical windows while assessing a spectrum of pubertal markers as outcomes. Coupled with comparative species studies, such research may provide insight regarding the causal ordering of events that underlie pubertal onset and progression and their role in the pathway of adult-onset disease.

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“…Acting within diverse cellular subsets, TTF1 enhances the transcriptional activity of genes required for the facilitatory control of gonadotropin secretion (GnRH, erbB2, KiSS1), while repressing the transcription of a gene involved in the inhibition of GnRH neuronal function (preproenkephalin) (39,40). Conditional deletion of the Ttf1 gene in differentiated neurons resulted in delayed female puberty, irregular estrous cyclicity, reduced reproductive capacity, and a shortened reproductive span, demonstrating the importance of this regulatory pathway for the normalcy of female reproductive function (40).…”

Section: Figurementioning

confidence: 99%

Enhanced at puberty 1 (EAP1) is a new transcriptional regulator of the female neuroendocrine reproductive axis

Heger¹,

Mastronardi²,

Dissen³

et al. 2007

J. Clin. Invest.

110

166

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The initiation of mammalian puberty and the maintenance of female reproductive cycles are events controlled by hypothalamic neurons that secrete the decapeptide gonadotropin-releasing hormone (GnRH). GnRH secretion is, in turn, controlled by changes in neuronal and glial inputs to GnRH-producing neurons. The hierarchical control of the process is unknown, but it requires coordinated regulation of these cell-cell interactions. Here we report the functional characterization of a gene (termed enhanced at puberty 1 [EAP1]) that appears to act as an upstream transcriptional regulator of neuronal networks controlling female reproductive function. EAP1 expression increased selectively at puberty in both the nonhuman primate and rodent hypothalamus. EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity. Inhibition of EAP1 expression, targeted to the rodent hypothalamus via lentivirusmediated delivery of EAP1 siRNAs, delayed puberty, disrupted estrous cyclicity, and resulted in ovarian abnormalities. These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function.

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Deletion of theTtf1Gene in Differentiated Neurons Disrupts Female Reproduction without Impairing Basal Ganglia Function

Cited by 68 publications

References 75 publications

Expression of a Tumor-Related Gene Network Increases in the Mammalian Hypothalamus at the Time of Female Puberty

Expression of a Tumor-Related Gene Network Increases in the Mammalian Hypothalamus at the Time of Female Puberty

Environmental Factors and Puberty Timing: Expert Panel Research Needs

Enhanced at puberty 1 (EAP1) is a new transcriptional regulator of the female neuroendocrine reproductive axis

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