Discovering the Effects of Intrinsic and Extrinsic Signals on the Developing Pituitary Gland

Ge, Xiyu

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https://hdl.handle.net/2142/117786 Copy

Description

Title

Discovering the Effects of Intrinsic and Extrinsic Signals on the Developing Pituitary Gland

Author(s)

Ge, Xiyu

Issue Date

2022-12-02

Director of Research (if dissertation) or Advisor (if thesis)

Raetzman, Lori

Doctoral Committee Chair(s)

Raetzman, Lori

Committee Member(s)

• Nelson, Erik
• Flaws, Jodi
• Christian-Hinman, Catherine

Department of Study

Molecular & Integrative Physl

Discipline

Molecular & Integrative Physi

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

Pituitary development

Abstract

The pituitary gland acts as a “master gland” of the endocrine system and mediates multiple physiological processes. Dysfunctions in pituitary development can lead to hypopituitarism, a deficiency in pituitary hormone secretion that causes disrupted endocrine functions. Intrinsic signals including sequential expression of transcription factors and activation of multiple signaling pathways, as well as extrinsic signals including hormone signals from other endocrine glands and exposure to endocrine disrupting chemicals are two regulators for pituitary development. Understanding of the mechanisms by which the intrinsic and extrinsic signals regulate the pituitary development is necessary for us to understand the proper functioning of the gland, and thus help us to develop treatments for hypopituitarism. The NOTCH signaling pathway has been known to be an intrinsic regulator of pituitary development and our lab’s previous studies have indicated that it’s necessary for pituitary stem cell renewal, maintenance, and differentiation. In this study, we identified a novel pituitary stem cell marker- glycoprotein hormone subunit alpha 2 (GPHA2), which we found to be regulated by NOTCH2, and we hypothesized it functions as a paracrine factor secreted by stem cells to regulate neighboring cells’ maintenance. We applied techniques including single cell RNA sequencing analysis, quantitative real-time PCR, in situ hybridization, immunohistochemistry, western blot, and pituitary explant/cell cultures. We identified GPHA2 signals through the thyroid stimulating hormone receptor (TSHR) signaling pathway in the pituitary and provided a target receptor for future investigations on GPHA2’s functions in the pituitary. Di(2-ethylhexyl) phthalate (DEHP) is an endocrine disrupting chemical (EDC) that’s known to interfere with reproductive functions. In this study, we investigated DEHP’s impacts as an extrinsic signal on the developing pituitary gland. We hypothesized DEHP activates aryl hydrocarbon receptor (AhR) signaling pathway in the pituitary and impacts gonadotroph functions. We performed in vivo dosing and in vitro pituitary explant culture, with analysis techniques including quantitative real-time PCR and dual-luciferase reporter assay. We reported DEHP (and its primary metabolite mono(2-ethylhexyl) phthalate, MEHP) to have both systemic and direct actions on the pituitary gland. Specifically, we found MEHP activates AhR signaling directly on the pituitary and caused a decrease in gonadotropin expression. Although we found no direct association between AhR activation and the reduction in gonadotropin expression, our study provided a direction for future studies in terms understanding the regulation of gonadotroph development and functions, possibly in relation to AhR signaling pathway in the pituitary.

Graduation Semester

2022-12

Type of Resource

Thesis

Copyright and License Information

Copyright 2022 Xiyu Ge

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