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Home > Program in Developmental Endocrinology and Genetics

Program in Developmental Endocrinology and Genetics

Director: Constantine A. Stratakis, MD, D(med)Sci

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The mission of the Program on Developmental Endocrinology and Genetics (PDEGEN) is to carry out translational research that addresses a wide spectrum of issues that converge in endocrine and genetic disorders, with particular emphasis on disorders of development, growth, and puberty. PDEGEN investigators have equally diverse backgrounds that range from biochemistry to molecular endocrinology and genetics to clinical obesity research.

In addition to Drs. Aguilera, Baron, Bondy, Catt, Chou, Dufau, Klein, Mukherjee, Owens, Porter, Stratakis and Yanovski, all tenured investigators, in 2010, two new research programs were added in PDEGEN: those headed by Dr. Joan Han and Maya Lodish who were both appointed as Assistant Clinical Investigators (ACIs) in PDEGEN, starting July 1st, 2010.

Greti Aguilera's Section on Endocrine Physiology focuses on the molecular mechanisms of the hypothalamic stress response. Research during the past year has yielded novel information on the transcriptional regulation of corticotropin releasing hormone (CRH) and the physiological actions of vasopressin (VP) during chronic stress adaptation. Contrary to the conventional view, Aguilera found that phosphorylation of the transcription factor CREB is not sufficient for activation of CRH transcription. Concerning the effects of VP, new findings demonstrate novel roles for the prominent increases in vasopressinergic activity during chronic stress. In addition to minor effects modulating pituitary adrenocorticotropic hormone secretion, the Section found that vasopressin mediates mitogenic responses in the pituitary and anti-apoptotic actions in the brain.

Jeffrey Baron's Section on Growth and Development investigates the cellular and molecular mechanisms governing longitudinal bone growth in childhood. Baron has developed a novel technique that allows quantitative assessment of gene expression within individual zones of the growth plate. This approach, combined with functional studies, has provided evidence that a bonemorphogenetic signaling gradient across the growth plate provides a key mechanism for chondrocyte differentiation. Analogous studies have provided insight into the roles of fibroblast growth factor and insulin-like growth factor signaling in the spatial and temporal regulation of growth plate chondrogenesis.

Carolyn Bondy's Section on Women's Health primarily studies Turner syndrome and its cardiovascular effects in late age. Pioneering the use of high-resolution magnetic resonance angiography (MRA) in this syndrome, Bondy demonstrated cardiovascular anomalies in about half of study subjects. Whereas congenital heart defects in Turner syndrome were thought to be limited to left-sided, outflow-tract defects, MRA revealed a high prevalence of major venous malformations, including partial anomalous pulmonary venous return and persistent left superior vena cava affecting over 20 percent of the study population. Bondy also described a new aortic abnormality that seems to be predictive of aortic complications in Turner syndrome. Bondy is considered the world's leading expert in adult complications of Turner syndrome.

Kevin Catt's Section on Hormonal Regulation investigates the molecular mechanisms of activation, signaling, and function of G protein–coupled receptors, particularly those for angiotensin II (AT1R and AT2R) and gonadotropin-releasing hormone (GnRHR), and the receptors' interactions with the epidermal growth factor receptor (EGFR). The Section identified specific and shared signaling pathways and interactions between the AT1R and EGFR and their dependence on caveolin. In addition, the Section identified Invariant Chain (Ii/CD74) as a novel interacting protein of the AT1R and as a negative regulator of its expression. Pulsatile neurosecretion by GnRH neurons appears to depend on the neurons' endogenous GIRK channels, activation of which prevents the firing of action potentials and inhibits episodic GnRH release. GPR54, the receptor that mediates kisspeptin induced activation of GnRH secretion, and GnRHR appear to form heterodimers in GnRH neurons. The Section also investigates the mechanisms by which GnRH activates several G proteins in the GnRH neuron. Current studies on GFP-expressing GnRH neurons address the regulatory roles of endogenous estrogen receptor subtypes in the control of GnRH secretion.

Janice Chou's Section on Cellular Differentiation studies glycogen storage disease type I (GSD-I), which is caused by deficiencies in the glucose-6-phosphatase-alpha (G6Pase-alpha)–glucose-6-phosphate transporter (G6PT) complex. The deficiencies result in disturbed glucose homeostasis; GSD-Ib also presents with myeloid dysfunctions. Chou showed that an increase in cellular cholesterol efflux and antioxidant capacity in the sera of GSD-Ia patients may protect against premature atherosclerosis. Using G6PT−/− mice, the Section showed that myeloid dysfunctions in GSD-Ib are intrinsically linked to G6PT deficiency in the bone marrow and neutrophils and that an adenoviral vector–mediated gene transfer improved metabolic and myeloid functions. The Section has recently characterized a G6Pase-alpha isoform, G6Pase-beta, that is expressed ubiquitously, as is G6PT. The Section showed that G6Pase-beta–null mice manifest myeloid dysfunctions mimicking GSD-Ib and that G6Pase-beta–deficient neutrophils undergo ER stress and an enhanced rate of apoptosis. The results demonstrate that a functional G6Pase-beta–G6PT complex is critical for neutrophil function, defining a molecular pathway to neutropenia and neutrophil dysfunction of unknown etiology.

Maria Dufau's Section on Molecular Endocrinology investigates the molecular basis of hormonal regulation of gonadal function, focusing on (1) modes of transcriptional repression and derepression of receptors for human luteinizing hormone (LHR) and prolactin (PRLR) and (2) the functions of novel short PRLR inhibitory forms, identified by the Section, in physiological regulation and cancer. The Section also investigates mechanisms involved in Leydig cell function and the progression of spermatogenesis. Recent studies revealed cell-specific contributions of phosphatases (PP2A and PP1) in activation of LHR transcription. Release of a phosphatase by changes in chromatin structure favors phosphorylation of Sp1 by PI3K/ PKCζ, causing release of p107 inhibitor and transcriptional activation of the LHR. Other studies demonstrated conformational determinants required for the inhibitory action of the PRLR short form on prolactin-induced signaling through the long form. Studies on the gonadotropin-regulated testicular helicase (GRTH/Ddx25), a protein discovered by this Section and shown to be essential for completion of spermatogenesis, demonstrated the protein's multifunctionality in nuclear transport, storage/degradation of messages, and translation. A missense mutation (Arg242H) of GRTH was found in infertile patients, and its expression revealed lack of the phosphorylated form, which could be relevant to functional aspects of this protein that affect germ cell development and/or function.

David Klein's Section on Neuroendocrinology has played a dominant role in the circadian and pineal fields, maintaining a focus on the key regulatory enzyme arylalkylamine N-acetyltransferase. Recently, the Section's interests broadened to characterize the pineal transcriptome. Studies use cDNA microarrays to investigate the regulatory cascades that determine cell fate and maintain phenotype, in addition to the cascades dedicated to control of the daily global changes in gene expression. The daily changes involve nearly 1,000 genes, some of which exhibit 100-fold night/day differences in expression. Klein's Section uses a variety of approaches to analyze the cascades, including conditional knockouts and RNAi strategies. An initiative recently undertaken by the Section is characterizing the microRNAs expressed in the pineal gland in order to determine their role in controlling the pineal transcriptome. The Section has initiated collaborations with other PDEG researchers in an effort to extend the PDEG's analysis of melatonin to clinical studies, with the ultimate goal of facilitating the analysis of circadian function.

Anil Mukherjee's Section on Developmental Genetics conducts both laboratory and clinical investigations to understand the molecular mechanism(s) of heritable childhood neurodegenerative diseases and inflammatory/autoimmune disorders. Investigations focus primarily on two genes: palmitoyl-protein thioesterase-1, mutation of which causes infantile Batten disease (IBD), and uteroglobin (UG), an anti-inflammatory protein. UG-knockout mice develop IgA-nephropathy, allergic airway inflammation, and tumor susceptibility. During the past year, the Section showed that (1) in PPT1-KO mice, a model for IBD, increased cystolic phospholipase A2–catalyzed production of lysophosphatidylcholine in the brain mediated microglial recruitment and activation; (2) oxidative and ER stress are common manifestations of both neurodegenerative and non-neurodegenerative storage disorders; and (3) mice lacking UG are highly susceptible to pulmonary fibrosis. The Section is continuing a clinical trial to determine if a combined regimen of Cystagon™ and N-acetylcysteine (Mucomyst®) is beneficial for patients with IBD.

Ida Owens' Section on Genetic Disorders of Drug Metabolism studies UDP-glucuronosyltransferase (UGT) isozymes that detoxify numerous endogenous and exogenous chemical toxins/mutagens found in our daily diet and environment. Extending its earlier discovery that all UGTs require phosphorylation, the Section determined that UGT1A7 and UGT1A10 phosphorylations are ongoing processes, each mediated by PKCε and PKCα/δ signal transduction, respectively. Owens has shown that the UGT2B family isozymes UGT2B7 and UGT2B15, which detoxify endogenous genotoxic catechol estrogens and dysfunctional prostate–causing dihydrotestosterone (DHT), respectively, require tyrosine phosphorylation, with UGT2B15 also requiring serine/threonine phosphorylation. Src–tyrosine kinase phosphorylation of UGT2B7 is lost in breast tumors; UGT2B7 capacity to detoxify genotoxic catechol estrogens is dependent on active Src in these tissues. The Section found that curcumin reversibly downregulated UGT phosphorylation in antigen-stimulated mice such that, when treated with the immunosuppressant mycophenolic acid (MPA), which is widely used for renal transplant patients, the mice exhibited a substantial increase in both free circulating MPA and immunosuppression. Thus, glucuronidation can markedly compromise drug efficacy while transient downregulation of UGT phosphorylation can have a significant effect on the efficacy of glucuronidatable drugs.

Forbes Porter's Section on Molecular Dysmorphology studies a group of human and mouse malformation syndromes attributable to inborn errors of cholesterol synthesis. The most common of these disorders is the Smith-Lemli-Opitz syndrome (SLOS). The Section studies both basic science and clinical aspects of SLOS, with the goal of developing and testing therapeutic interventions for SLOS. A clinical trial evaluating the safety and efficacy of simvastatin therapy in SLOS has completed enrollment. This past year, the Section received a Bench-to-Bedside award to investigate the role of impaired glycosphingolipid transport in SLOS. The Section also continues to study other inborn errors of cholesterol synthesis and recently described the biochemical and phenotypic consequences of disrupting sterol Δ14-reductase. Over the past year, the Section initiated a clinical study of patients with Niemann-Pick disease, type C (NPC), a neurodegenerative disorder caused by impaired intracellular transport of cholesterol and glycosphingolipids. The protocol is designed to investigate biochemical markers and clinical aspects of NPC that could potentially be used as outcome measures in a future clinical trial.

Constantine Stratakis' Section on Endocrinology and Genetics investigates the genetic and molecular mechanisms leading to disorders affecting the adrenal cortex, with emphasis on those that are developmental, hereditary, and associated with adrenal hypoplasia or hyperplasia, multiple tumors, and abnormalities in other endocrine glands (especially the pituitary gland and, to a lesser extent, the thyroid gland). The Section has studied congenital adrenal hypoplasia caused by triple A syndrome; several endocrine deficiencies; familial hyperaldosteronism; adrenocortical and thyroid cancer; pituitary tumors; multiple endocrine neoplasia (MEN) syndromes affecting the pituitary, thyroid, and adrenal glands; and Carney complex (CNC), an autosomal dominant disease. Stratakis and colleagues first identified the regulatory subunit type 1-α (RIα) of protein kinase A (PKA) (the PRKAR1A gene), which is mutated in most CNC patients. Most recently, the Section found phosphodiesterase-11A (PDE11A) mutations in patients with isolated adrenal hyperplasia and Cushing syndrome. A significant part of the Section's work focuses on cyclic AMP (cAMP)/PKA–stimulated signaling pathways, PKA effects on tumor suppression, and/or development and the cell cycle. The Section's various studies take advantage of prkar1a and pde11a gene mouse models, in which the respective genes have been knocked out. Genome-wide searches for other genes responsible for CNC and related diseases of the adrenal, pituitary and other endocrine glands are ongoing.

Jack Yanovski's Section on Growth and Obesity studies metabolic and behavioral factors involved in body weight regulation and body composition during childhood. The Section is investigating the effects of several genetic mutations in human pediatric obesity and murine models. The Unit has also investigated the role played by brain-derived neurotrophic factor (BDNF) in overweight children. Ongoing studies attempt to identify genetic abnormalities that predispose children to binge eating and related disorders.

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