Transforming growth factor alpha contributes to the mechanism by which hypothalamic injury induces precocious puberty.

Junier, Marie Pierre; Jin, Ying; Costa, Maria E.; Hoffman, Gloria E.; Hill, Douglas; Ojeda, Sergio R.

doi:10.1073/pnas.88.21.9743

Cited by 95 publications

(56 citation statements)

References 30 publications

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“…[67,72,112,113] Evidence exists that the local activation of astrocytes in these models is mediated by cytokines and growth factors including interleukin (IL)-1, IL-6, transforming growth factor-alpha, transforming growth factor-beta1, tumor necrosis factor-alpha, gamma-interferon, and basic fibroblast growth factor. [2,31,32,33,40,53,58,82,119,120] Interestingly, astrocytes have the highest predisposition to malignant transformation of any CNS cell type. The astrocytoma is the most common brain tumor arising in the CNS, accounting for 65% of all primary brain tumors.…”

Section: Biological Features Of Astrocytesmentioning

confidence: 99%

Role of glial filaments in cells and tumors of glial origin: a review

Rutka¹,

Murakami²,

Dirks³

et al. 1997

FOC

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In the adult human brain, normal astrocytes constitute nearly 40% of the total central nervous system (CNS) cell population and may assume a star-shaped configuration resembling epithelial cells insofar as the astrocytes remain intimately associated, through their cytoplasmic extensions, with the basement membrane of the capillary endothelial cells and the basal lamina of the glial limitans externa. Although their exact function remains unknown, in the past, astrocytes were thought to subserve an important supportive role for neurons, providing a favorable ionic environment, modulating extracellular levels of neurotransmitters, and serving as spacers that organize neurons. In immunohistochemical preparations, normal, reactive, and neoplastic astrocytes may be positively identified and distinguished from other CNS cell types by the expression of the astrocyte-specific intermediate filament glial fibrillary acidic protein (GFAP). This GFAP is a 50-kD intracytoplasmic filamentous protein that constitutes a portion of, and is specific for, the cytoskeleton of the astrocyte. This protein has proved to be the most specific marker for cells of astrocytic origin under normal and pathological conditions. Interestingly, with increasing astrocytic malignancy, there is progressive loss of GFAP production. As the human gene for GFAP has now been cloned and sequenced, this review begins with a summary of the molecular biology of GFAP including the proven utility of the GFAP promoter in targeting genes of interest to the CNS in transgenic animals. Based on the data provided the authors argue cogently for an expanded role of GFAP in complex cellular events such as cytoskeletal reorganization, maintenance of myelination, cell adhesion, and signaling pathways. As such, GFAP may not represent a mere mechanical integrator of cellular space, as has been previously thought. Rather, GFAP may provide docking sites for important kinases that recognize key cellular substrates that enable GFAP to form a dynamic continuum with microfilaments, integrin receptors, and the extracellular matrix.

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Section: Biological Features Of Astrocytesmentioning

confidence: 99%

Role of glial filaments in cells and tumors of glial origin: a review

Rutka¹,

Murakami²,

Dirks³

et al. 1997

FOC

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“…The hybridization procedure used was that recommended by Simmons et al (22) and previously used by us (23,24). Control sections were incubated with a sense probe transcribed from the same plasmid, but linearized on the 3Ј end to transcribe the coding strand of the cDNA template.…”

Section: In Situ Hybridizationmentioning

confidence: 99%

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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“…While blockade of EGF͞TGF␣ receptors targeted to the ME delays puberty (4), transgenic mice overexpressing the TGF␣ gene under the control of a metallothionein (MT) promoter respond to activation of the promoter with LHRH release and acceleration of sexual development (7). Hypothalamic lesions that result in activation of TGF␣ expression in reactive astrocytes surrounding the site of injury advance puberty when located near LHRH neurons (5). These and other observations have led to the concept that activation of TGF␣ expression in glial cells located near LHRH neurons results in stimulation of further TGF␣ production from adjacent astrocytes via a paracrine route (8) and the subsequent release of neuroactive substances of glial origin able to stimulate LHRH secretion, such as prostaglandin E 2 (PGE 2 ) (9).…”

mentioning

confidence: 99%

“…Recent studies, performed in laboratory animals and nonhuman primates, have suggested that growth factors of the epidermal growth factor (EGF) family, and in particular transforming growth factor ␣ (TGF␣), produced by glial cells of the neuroendocrine brain, are involved in the developmental process that controls both normal and premature sexual maturation (4)(5)(6). Studies in rats showed that in normal puberty, TGF␣ expression increases mainly in the median eminence (ME) of the hypothalamus (where neuroendocrine LHRH neurons send their axons) and the preoptic-suprachiasmatic area (where many LHRH neuronal perikarya are located) (4).…”

mentioning

confidence: 99%

Targeting transforming growth factor α expression to discrete loci of the neuroendocrine brain induces female sexual precocity

Rage

Hill

Sena‐Esteves

et al. 1997

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

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Precocious puberty of cerebral origin is a poorly understood disorder of human sexual development, brought about by the premature activation of those neurons that produce luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual maturation. An increased production of transforming growth factor ␣ (TGF␣) in the hypothalamus has been implicated in the mechanism underlying both normal and precocious puberty. We have now used two gene delivery systems to target TGF␣ overexpression near LHRH neurons in immature female rats. Fibroblasts infected with a retroviral construct in which expression of the human TGF␣ gene is constitutively driven by the phosphoglycerate kinase promoter, or transfected with a plasmid in which TGF␣ expression is controlled by an inducible metallothionein promoter, were transplanted into several regions of the hypothalamus. When the cells were in contact with LHRH nerve terminals or in the vicinity of LHRH perikarya, sexual maturation was accelerated. These results suggest that precocious puberty of cerebral origin may result from a focal disorder of TGF␣ production within the confines of the LHRH neuron microenvironment.The initiation of mammalian puberty requires the activation of a group of highly specialized neurons located in the basal forebrain that produce luteinizing hormone-releasing hormone (LHRH), the decapeptide controlling sexual development and mature reproductive function (1). Hypothalamic lesions that presumably cause premature activation of LHRH neurons result in sexual precocity (2), a disorder that in human females may occur as early as the first year of life and is associated with an increased incidence of breast cancer and ovarian cysts in adulthood (3).Most cases of female sexual precocity of central origin are diagnosed as idiopathic, as evidence for organic disfunction of the brain is found in only a minority of patients (3). Recent studies, performed in laboratory animals and nonhuman primates, have suggested that growth factors of the epidermal growth factor (EGF) family, and in particular transforming growth factor ␣ (TGF␣), produced by glial cells of the neuroendocrine brain, are involved in the developmental process that controls both normal and premature sexual maturation (4-6). Studies in rats showed that in normal puberty, TGF␣ expression increases mainly in the median eminence (ME) of the hypothalamus (where neuroendocrine LHRH neurons send their axons) and the preoptic-suprachiasmatic area (where many LHRH neuronal perikarya are located) (4). While blockade of EGF͞TGF␣ receptors targeted to the ME delays puberty (4), transgenic mice overexpressing the TGF␣ gene under the control of a metallothionein (MT) promoter respond to activation of the promoter with LHRH release and acceleration of sexual development (7). Hypothalamic lesions that result in activation of TGF␣ expression in reactive astrocytes surrounding the site of injury advance puberty when located near LHRH neurons (5). These and other observations have led to the concep...

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Transforming growth factor alpha contributes to the mechanism by which hypothalamic injury induces precocious puberty.

Cited by 95 publications

References 30 publications

Role of glial filaments in cells and tumors of glial origin: a review

Role of glial filaments in cells and tumors of glial origin: a review

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

Targeting transforming growth factor α expression to discrete loci of the neuroendocrine brain induces female sexual precocity

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