Date of Award

Summer 2022

Document Type

Open Access Dissertation

Department

Biological Sciences

First Advisor

Shannon Davis

Second Advisor

Sofia Lizarraga

Abstract

Human development is tightly regulated by complex mechanisms to pattern the early embryo and form specialized tissues. Understanding this regulation is of fundamental importance and can help further understand disease pathologies. Because it is difficult to observe the processes of interest, researchers must rely on the use of model systems. Our research goal is to combine both animal models and in vitro stem cell cultures to address key questions about the mechanisms of development for both the pituitary gland and brain. It is estimated that there are 290-455 cases per million of congenital hypopituitarism. In addition, autism spectrum disorder (ASD) affects 1 in 44 children and represents a growing public health concern.

The pituitary gland is often referred to as the “master gland” because its hormones help regulate other endocrine glands, including the thyroid gland and adrenal glands. The pituitary organizer is a domain within the ventral diencephalon (VD) that expresses Bmp4, Fgf8, and Fgf10, which induce the formation of the pituitary progenitors that generate the hormone secreting cells of the pituitary anterior lobe. By utilizing gain-offunction and loss-of-function mouse models, we have established a role for WNT signaling for the proper expression of pituitary organizer genes and formation of pituitary progenitors. We also utilized human embryonic stem cells (hESCs) as an in vitro model for pituitary development and to manipulate BMP and FGF levels necessary for pituitary progenitor induction. While animal models have given us remarkable insight, significant differences exist between the murine and human systems. Stem cell derived models can overcome this limitation by providing a human platform to conduct molecular, cellular, or physiological studies.

Autism spectrum disorders (ASD) are associated with defects in neuronal connectivity and are highly heritable. ASH1 like histone lysine methyltransferase (ASH1L) was identified as a major risk factor for ASD. We utilized human stem cell derived cortical excitatory neurons to study neuronal development. Our work suggests that ASH1L epigenetically regulates neuronal morphogenesis by modulating the BDNFTrkB signaling pathway, which is necessary for axon formation. Defects in neuronal morphogenesis impair the establishment of neuronal connections, providing a mechanism for how ASH1L mutations causes ASD.

Rights

© 2022, Allison Culver

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