scholarly journals Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

2015 ◽  
Vol 2016 (1) ◽  
pp. 4-22 ◽  
Author(s):  
M. I. Stamou ◽  
K. H. Cox ◽  
William F. Crowley
Keyword(s):  
Human Disease ◽  
Hypogonadotropic Hypogonadism ◽  
Disease Model ◽  
Human Reproduction ◽  
Pathway Gene ◽  
Gnrh Neurons ◽  
Hypothalamic Regulation ◽  
Complex Life History ◽  
Traditional Approaches

Abstract The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamic-pituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the “known” genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3)substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery. (Endocrine Reviews 36: 603–621, 2015)

scholarly journals Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

2015 ◽  
Vol 36 (6) ◽  
pp. 603-621 ◽  
Author(s):  
M. I. Stamou ◽  
K. H. Cox ◽  
William F. Crowley
Keyword(s):  
Human Disease ◽  
Hypogonadotropic Hypogonadism ◽  
Disease Model ◽  
Human Reproduction ◽  
Pathway Gene ◽  
Gnrh Neurons ◽  
Hypothalamic Regulation ◽  
Complex Life History ◽  
Traditional Approaches

Abstract The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamic-pituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the “known” genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3) substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery.

On the emerging role of rabbit as human disease model and the instrumental role of novel transgenic tools

2012 ◽  
Vol 21 (4) ◽  
pp. 699-713 ◽  
Author(s):  
V. Duranthon ◽  
N. Beaujean ◽  
M. Brunner ◽  
K. E. Odening ◽  
A. Navarrete Santos ◽  
...  
Keyword(s):  
Human Disease ◽  
Disease Model ◽  
Transgenic Tools ◽  
Instrumental Role

scholarly journals Deletion of the Homeodomain Protein Six6 From GnRH Neurons Decreases GnRH Gene Expression, Resulting in Infertility

Endocrinology ◽  
2019 ◽  
Vol 160 (9) ◽  
pp. 2151-2164 ◽  
Author(s):  
Erica C Pandolfi ◽  
Karen J Tonsfeldt ◽  
Hanne M Hoffmann ◽  
Pamela L Mellon
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Neuronal Cell ◽  
Delayed Puberty ◽  
Homeodomain Protein ◽  
Gnrh Neuron ◽  
Direct Role ◽  
Hpg Axis ◽  
Gnrh Neurons

Abstract Hypothalamic GnRH (luteinizing hormone–releasing hormone) neurons are crucial for the hypothalamic-pituitary-gonadal (HPG) axis, which regulates mammalian fertility. Insufficient GnRH disrupts the HPG axis and is often associated with the genetic condition idiopathic hypogonadotropic hypogonadism (IHH). The homeodomain protein sine oculis–related homeobox 6 (Six6) is required for the development of GnRH neurons. Although it is known that Six6 is specifically expressed within a more mature GnRH neuronal cell line and that overexpression of Six6 induces GnRH transcription in these cells, the direct role of Six6 within the GnRH neuron in vivo is unknown. Here we find that global Six6 knockout (KO) embryos show apoptosis of GnRH neurons beginning at embryonic day 14.5 with 90% loss of GnRH neurons by postnatal day 1. We sought to determine whether the hypogonadism and infertility reported in the Six6KO mice are generated via actions within the GnRH neuron in vivo by creating a Six6-flox mouse and crossing it with the LHRHcre mouse. Loss of Six6 specifically within the GnRH neuron abolished GnRH expression in ∼0% of GnRH neurons. We further demonstrated that deletion of Six6 only within the GnRH neuron leads to infertility, hypogonadism, hypogonadotropism, and delayed puberty. We conclude that Six6 plays distinct roles in maintaining fertility in the GnRH neuron vs in the migratory environment of the GnRH neuron by maintaining expression of GnRH and survival of GnRH neurons, respectively. These results increase knowledge of the role of Six6 in the brain and may offer insight into the mechanism of IHH.

scholarly journals Kisspeptin/GPR54 System: What Do We Know About Its Role in Human Reproduction?

2018 ◽  
Vol 49 (4) ◽  
pp. 1259-1276 ◽  
Author(s):  
Camila M. Trevisan ◽  
Erik Montagna ◽  
Renato de Oliveira ◽  
Denise M. Christofolini ◽  
Caio P. Barbosa ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Controlled Ovarian Hyperstimulation ◽  
Human Reproduction ◽  
Feedback Mechanisms ◽  
Activating Mutations ◽  
Sexual Steroids ◽  
Literature Searches ◽  
The Impact ◽  
G Protein Coupled

Kisspeptin is involved in the control of human reproduction bridging the gap between the sex steroid levels and feedback mechanisms that control the gonadotropin releasing hormone (GnRH) secretion; however, studies considering this peptide and infertility are limited. We conducted a review and critical assessment of available evidence considering kisspeptin structure, physiology, function in puberty and reproduction, its role in assisted reproduction treatments, kisspeptin dosage and the impact on KISS1 and GPR54 genes. Literature searches were conducted in PubMed using keywords related to: (i) kisspeptin or receptors, kisspeptin-1 (ii) reproduction or infertility or fertility (iii) gene and (iv) dosage or measurement or quantification or serum level, in human. Kisspeptin is a product of KISS1 gene that binds to a G-protein-coupled receptor (GPR54/KISS1R) stimulating the release of GnRH by hypothalamic neurons, leading to secretion of pituitary gonadotropins (LH and FSH) and sexual steroids, which in turn will act in the gonads to produce the gametes. Kisspeptin is being recognized as a crucial regulator of the onset of puberty, the regulation of sex hormone mediated secretion of gonadotropins, and the control of fertility. Inactivating and activating mutations in both KISS1 or GPR54 genes were associated with hypogonadotropic hypogonadism and precocious puberty. Despite this, studies considering kisspeptin and infertility are scarce. The understanding of the role of kisspeptin may lead to its use as a biomarker in infertility treatments and use in controlled ovarian hyperstimulation.

E-Projects Challenges in India – Role of Human Resource Management and Technology

2018 ◽  
Vol 6 (8) ◽  
pp. 263
Author(s):  
Ramnik Kaur
Keyword(s):  
Developing Countries ◽  
Public Administration ◽  
Paradigm Shift ◽  
Successful Implementation ◽  
The Public ◽  
Government Services ◽  
The Past ◽  
The Government ◽  
Traditional Approaches

E-governance is a paradigm shift over the traditional approaches in Public Administration which means rendering of government services and information to the public by using electronic means. In the past decades, service quality and responsiveness of the government towards the citizens were least important but with the approach of E-Government the government activities are now well dealt. This paper withdraws experiences from various studies from different countries and projects facing similar challenges which need to be consigned for the successful implementation of e-governance projects. Developing countries like India face poverty and illiteracy as a major obstacle in any form of development which makes it difficult for its government to provide e-services to its people conveniently and fast. It also suggests few suggestions to cope up with the challenges faced while implementing e-projects in India.

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