Transcriptional Regulatory Role of NELL2 in Preproenkephalin Gene Expression.

Preproenkephalin (PPE) is a precursor molecule for multiple endogenous opioid peptides Leu-enkephalin (ENK) and Met-ENK, which are involved in a wide variety of modulatory functions in the nervous system. Despite the functional importance of ENK in the brain, the effect of brain-derived factor(s) on PPE expression is unknown. We report the dual effect of neural epidermal growth factor (EGF)-likelike 2 (NELL2) on PPE gene expression.

DLK1: A Novel Biomarker of Placental Insufficiency in Stillbirth and Live Birth.

Objective: Delta-like homolog 1 (DLK1) is a growth factor that is reduced in maternal sera in pregnancies with small for gestational age neonates. We sought to determine if DLK1 is associated with stillbirth (SB), with and without placental insufficiency.

Study Design: A nested case-control study was performed using maternal sera from a multicenter case-control study of SB and live birth (LB).

GnRH neurons recruit astrocytes in infancy to facilitate network integration and sexual maturation.

Neurons that produce gonadotropin-releasing hormone (GnRH), which control fertility, complete their nose-to-brain migration by birth. However, their function depends on integration within a complex neuroglial network during postnatal development. Here, we show that rodent GnRH neurons use a prostaglandin D receptor DP1 signaling mechanism during infancy to recruit newborn astrocytes that 'escort' them into adulthood, and that the impairment of postnatal hypothalamic gliogenesis markedly alters sexual maturation by preventing this recruitment, a process mimicked by the endocrine disruptor bisphenol A.

EAP1 regulation of GnRH promoter activity is important for human pubertal timing.

The initiation of puberty is orchestrated by an augmentation of gonadotropin-releasing hormone (GnRH) secretion from a few thousand hypothalamic neurons. Recent findings have indicated that the neuroendocrine control of puberty may be regulated by a hierarchically organized network of transcriptional factors acting upstream of GnRH. These include enhanced at puberty 1 (EAP1), which contributes to the initiation of female puberty through transactivation of the GnRH promoter.

SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression.

Puberty is regulated by epigenetic mechanisms and is highly sensitive to metabolic and nutritional cues. However, the epigenetic pathways mediating the effects of nutrition and obesity on pubertal timing are unknown. Here, we identify Sirtuin 1 (SIRT1), a fuel-sensing deacetylase, as a molecule that restrains female puberty via epigenetic repression of the puberty-activating gene, Kiss1.

Correcting deregulated Fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na, K-ATPase activity (NKA), an excess of Fxyd1 may reduce NKA activity and contribute to the neuronal phenotype of Mecp2 deficient (KO) mice.

Hypothalamic epigenetics driving female puberty.

Puberty involves a series of morphological, physiological and behavioural changes during the last part of the juvenile period that culminates in the attainment of fertility. The activation of the pituitary-gonadal axis by increased hypothalamic secretion of gonadotrophin-releasing hormone (GnRH) is an essential step in the process. The current hypothesis postulates that a loss of transsynaptic inhibition and a rise in excitatory inputs are responsible for the activation of GnRH release.

Trithorax dependent changes in chromatin landscape at enhancer and promoter regions drive female puberty.

Polycomb group (PcG) proteins control the timing of puberty by repressing the Kiss1 gene in hypothalamic arcuate nucleus (ARC) neurons. Here we identify two members of the Trithorax group (TrxG) of modifiers, mixed-lineage leukemia 1 (MLL1), and 3 (MLL3), as central components of an activating epigenetic machinery that dynamically counteracts PcG repression. Preceding puberty, MLL1 changes the chromatin configuration at the promoters of Kiss1 and Tac3, two genes required for puberty to occur, from repressive to permissive.

Reproductive Science for High School Students: A Shared Curriculum Model to Enhance Student Success.

The lack of a national reproductive biology curriculum leads to critical knowledge gaps in today's high school students' comprehensive understanding of human biology. The Oncofertility Consortium developed curricula that address the basic and clinical aspects of reproductive biology. Launching this academy and creating easy-to-disseminate learning modules allowed other universities to implement similar programs across the country.

Human Endometrial Fibroblasts Derived from Mesenchymal Progenitors Inherit Progesterone Resistance and Acquire an Inflammatory Phenotype in the Endometrial Niche in Endometriosis.

Human endometrium undergoes cyclic regeneration involving stem/progenitor cells, but the role of resident endometrial mesenchymal stem cells (eMSC) as progenitors of endometrial stromal fibroblasts (eSF) has not been definitively demonstrated. In endometriosis, eSF display progesterone (P4) resistance with impaired decidualization in vivo and in vitro. To investigate eMSC as precursors of eSF and whether endometriosis P4 resistance is inherited from eMSC, we analyzed transcriptomes of eutopic endometrium eMSC and eSF isolated by fluorescence-activated cell sorting (FACS) from endometriosis (eMSCendo, eSFendo) and controls (eMSCcontrol, eSFcontrol) and their derived primary cultures.

Kisspeptin receptor haplo-insufficiency causes premature ovarian failure despite preserved gonadotropin secretion.

Premature ovarian failure (POF) affects 1% of women in reproductive age, but its etiology remains uncertain. Whereas kisspeptins, the products of Kiss1 that act via Kiss1r (aka, Gpr54), are known to operate at the hypothalamus to control GnRH/gonadotropin secretion, additional actions at other reproductive organs, including the ovary, have been proposed. Yet, their physiological relevance is still unclear.

Loss of Ntrk2/Kiss1r signaling in oocytes causes premature ovarian failure.

Neurotrophins (NTs), once believed to be neural-specific trophic factors, are now known to also provide developmental cues to non-neural cells. In the ovary, NTs contribute to both the formation and development of follicles. Here we show that oocyte-specific deletion of the Ntrk2 gene that encodes the NTRK2 receptor (NTRK2) for neurotrophin-4/5 and brain-derived neurotrophic factor (BDNF) results in post-pubertal oocyte death, loss of follicular organization, and early adulthood infertility.

An alternative transcription start site yields estrogen-unresponsive Kiss1 mRNA transcripts in the hypothalamus of prepubertal female rats.

The importance of the Kiss1 gene in the control of reproductive development is well documented. However, much less is known about the transcriptional regulation of Kiss1 expression in the hypothalamus. Critical for these studies is an accurate identification of the site(s) where Kiss1 transcription is initiated.

Applying gene silencing technology to contraception.

Population control of feral animals is often difficult, as it can be dangerous for the animals, labour intensive and expensive. Therefore, a useful tool for control of animal populations would be a non-surgical method to induce sterility. Our laboratories utilize methods aimed at targeting brain cells in vivo with vehicles that deliver a payload of either inhibitory RNAs or genes intended to correct cellular dysfunction.

Correcting deregulated Fxyd1 expression ameliorates a behavioral impairment in a mouse model of Rett syndrome.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the MECP2. Several genes have been shown to be MECP2 targets. We previously identified FXYD1 (encoding phospholemman; a protein containing the motif phenylalanine-X-tyrosine-aspartate), a gene encoding a transmembrane modulator of the Na, K-ATPase (NKA) enzyme, as one of them.

Targeted gene silencing to induce permanent sterility.

A non-surgical method to induce sterility would be a useful tool to control feral populations of animals. Our laboratories have experience with approaches aimed at targeting brain cells in vivo with vehicles that deliver a payload of either inhibitory RNAs or genes intended to correct cellular dysfunction. A combination/modification of these methods may provide a useful framework for the design of approaches that can be used to sterilize cats and dogs.

Thyroid transcription factor 1, a homeodomain containing transcription factor, contributes to regulating periodic oscillations in GnRH gene expression.

Thyroid transcription factor 1 (TTF1), a member of the Nkx family of transcription factors required for basal forebrain morphogenesis, functions in the postnatal hypothalamus as a transcriptional regulator of genes encoding neuromodulators and hypophysiotrophic peptides. One of these peptides is gonadotrophin-releasing hormone (GnRH). In the present study, we show that Ttf1 mRNA abundance varies in a diurnal and melatonin-dependent fashion in the preoptic area of the rat, with maximal Ttf1 expression attained during the dark phase of the light/dark cycle, preceding the nocturnal peak in GnRH mRNA content.

Neurotrophins acting via TRKB receptors activate the JAGGED1-NOTCH2 cell-cell communication pathway to facilitate early ovarian development.

Tropomyosin-related kinase (TRK) receptor B (TRKB) mediates the supportive actions of neurotrophin 4/5 and brain-derived neurotrophic factor on early ovarian follicle development. Absence of TRKB receptors reduces granulosa cell (GC) proliferation and delays follicle growth. In the present study, we offer mechanistic insights into this phenomenon.

Excessive ovarian production of nerve growth factor elicits granulosa cell apoptosis by setting in motion a tumor necrosis factor α/stathmin-mediated death signaling pathway.

Excessive nerve growth factor (NGF) production by the ovary, achieved via a transgenic approach, results in arrested antral follicle growth, reduced ovulatory capacity, and a predisposition to cyst formation in response to mildly elevated LH levels. Two salient features in these mutant mice (termed 17NF) are an elevated production of 17α-hydroxyprogesterone (17-OHP(4)), testosterone, and estradiol (E(2)) in response to gonadotropins, and an increased frequency of granulosa cell (GC) apoptosis. In this study, we show that the increase in steroidal response is associated with enhanced expression of Cyp17a1, Hsd17b, and Cyp19a1, which encode the enzymes catalyzing the synthesis of 17-OHP(4), testosterone, and E(2) respectively.

Contribution of glial-neuronal interactions to the neuroendocrine control of female puberty.

Mammalian puberty is initiated by an increased pulsatile release of the neuropeptide gonadotropin-releasing hormone (GnRH) from hypothalamic neuroendocrine neurons. Although this increase is primarily set in motion by neuronal networks synaptically connected to GnRH neurons, glial cells contribute to the process via at least two mechanisms. One involves production of growth factors acting via receptors endowed with either serine-threonine kinase or tyrosine kinase activity.

The transcriptional control of female puberty.

The initiation of mammalian puberty requires a sustained increase in pulsatile release of gonadotrophin releasing hormone (GnRH) from the hypothalamus. This increase is brought about by coordinated changes in transsynaptic and glial-neuronal communication, consisting of an increase in neuronal and glial stimulatory inputs to the GnRH neuronal network and the loss of transsynaptic inhibitory influences. GnRH secretion is stimulated by transsynaptic inputs provided by excitatory amino acids (glutamate) and at least one peptide (kisspeptin), and by glial inputs provided by growth factors and small bioactive molecules.

Gene networks and the neuroendocrine regulation of puberty.

A sustained increase in pulsatile release of gonadotrophin releasing hormone (GnRH) from the hypothalamus is an essential, final event that defines the initiation of mammalian puberty. This increase depends on coordinated changes in transsynaptic and glial-neuronal communication, consisting of activating neuronal and glial excitatory inputs to the GnRH neuronal network and the loss of transsynaptic inhibitory tone. It is now clear that the prevalent excitatory systems stimulating GnRH secretion involve a neuronal component consisting of excitatory amino acids (glutamate) and at least one peptide (kisspeptin), and a glial component that uses growth factors and small molecules for cell-cell signaling.

In vivo manipulation of gene expression in non-human primates using lentiviral vectors as delivery vehicles.

Non-human primates (NHPs) are an invaluable resource for the study of genetic regulation of disease mechanisms. The main disadvantage of using NHPs as a preclinical model of human disease is the difficulty of manipulating the monkey genome using conventional gene modifying strategies. Lentiviruses offer the possibility of circumventing this difficulty because they can infect and transduce either dividing or nondividing cells, without producing an immune response.

Role of neurotrophic factors in early ovarian development.

Much is known about the endocrine hormonal mechanisms controlling ovarian development. More recently, attention has focused on identifying regulatory pathways that, operating within the ovarian microenvironment, contribute to the acquisition of ovarian reproductive competence. Within this framework, the concept has developed that neurotrophins (NTs) and their Trk tyrosine kinase receptors, long thought to be exclusively required for the development of the nervous system, are also involved in the control of ovarian maturation.