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Title:Uncovering novel actions of numb and aryl hydrocarbon receptor in the pituitary
Author(s):Moran, Tyler B.
Director of Research:Raetzman, Lori T.
Doctoral Committee Chair(s):Raetzman, Lori T.
Doctoral Committee Member(s):Katzenellenbogen, Benita S.; Kemper, Byron W.; Flaws, Jodi A.; Schantz, Susan L.
Department / Program:Molecular & Integrative Physl
Discipline:Molecular & Integrative Physi
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Numb
pituitary
Notch
Aryl hydrocarbon receptor (AhR or AHR)
Abstract:Many physiological responses are regulated by the pituitary including, but not limited to, growth, metabolism, response to stress, and fertility. These responses in the anterior lobe are mediated by the release of the following hormones, growth hormone (GH), adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), prolactin, (PRL), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), and in mice, an additional intermediate lobe produces alpha melanocyte-stimulating hormone (␣MSH) from alternative cleavage of the Pomc gene. The pituitary modulates many of these processes in a dynamic manner in response to physiological need. This includes not only adjusting hormone secretion, but can also include increasing cellular proliferation to meet greater demands. Taken together with the fact that these hormone producing cells differentiate in a spatial and temporal specific manner, the pituitary then is a convenient model to study cellular differentiation, endocrine cell localization, and progenitor cell maintenance. The present work identifies a novel endogenous function for the gene Numb, as well as both intrinsic and extrinsic effects of aryl hydrocarbon receptor activation, on pituitary hormone producing cells. The adaptor protein Numb was originally described as an important mediator of asymmetric cell division during neurogenesis, however in the study described here it is shown to have an important cell adhesion function in the post-natal pituitary. Both NUMB and related homolog NUMBLIKE, are expressed early in pituitary development before hormone cell specification, at which point they become undetectable by immunohistochemisty. NUMB expression becomes prominent again after birth in the ␣MSH expressing intermediate lobe cells, as well as the gonadotropes in the anterior lobe. Full Numb knockout mice (Numb-/-) are embryonic lethal before development of the pituitary, so the work described here utilized a Cre-loxP conditional knockout system driven off the Pomc promoter to delete Numb and Numblike in the intermediate lobe. Conditional double knockout animals (cDKO) have metaplastic intermediate lobes with impaired localization of adherens junctions proteins including N- and E-cadherin, and beta- and alpha-catenin, and strikingly, infiltration by arginine vasopressin secreting posterior lobe axons. Last, the Sox2 positive progenitor cell niche is disrupted such that these cells become more diffuse throughout the intermediate lobe rather than restricted to ii the luminal border of the intermediate lobe, as compared to controls. Numb then is critical for maintaining proper intermediate lobe cell adhesion and localization. A class of endocrine disruptors includes environmental dioxins, which act by binding the aryl hydrocarbon receptor (AhR). These compounds are known for causing fertility problems and cancer development, yet little is understood regarding the role of AhR in the mammalian pituitary. This work describes the effect of AhR activation on endogenous pituitary hormone expression and proliferation in the GH3 rat somato- lactrotroph cell line. The AhR agonist ␣-naphthoflavone at nanomolar doses impairs mRNA and protein expression of PRL, but not GH transcription in GH3 cells. Also, when combined with 100 nM of the partial AhR antagonist ␣-naphthoflavone, the suppressive effects on PRL were enhanced and GH levels remained unaffected. These changes coincide with a suppression of the anti-proliferative signaling cytokine TGFbeta1. In knockout studies, we find that female AhR-/- mice have significantly reduced LH expression at postnatal day 90. Overall, these results show AhR not only has important endogenous effects with respect to normal pituitary function, but also that exogenous stimulation through environmental contaminants could lead to significant suppression of pituitary hormones.
Issue Date:2011-05-25
URI:http://hdl.handle.net/2142/24432
Rights Information:Copyright 2011 Tyler B. Moran
Date Available in IDEALS:2011-05-25
2013-05-26
Date Deposited:2011-05


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