Date of Award

Fall 2023

Project Type

Dissertation

Program or Major

Biochemistry

Degree Name

Doctor of Philosophy

First Advisor

Xuanmao XC Chen

Second Advisor

Rick RC Cote

Third Advisor

Feixia FC Chu

Abstract

Cilia are microtubules-based, hair-like structures extending from the surface of cells. Cilia can be found in various parts of the body, including the central nervous system and the peripheral nervous system. Olfactory cilia, which are specialized immotile cilia located on the olfactory sensory neurons of the nasal cavity, are responsible for detecting and transmitting signals related to the sense of smell. Primary cilia, another type of immotile cilia that are present solitary in almost all mammalian cells, have emerged as crucial cell antennae that can sense extracellular chemical and mechanical signals. Although numerous studies have demonstrated that dysfunctions of primary cilia cause various neurological diseases, their roles in neurons remain poorly understood. My dissertation has two major aims. First, I sought to investigate how mammals perceive acid volatiles, elucidating the mechanisms underlying this olfactory sensory perception. Second, I aimed to unravel the roles of primary cilia in postnatal neurodevelopment in the central and peripheral nervous systems, respectively. Project 1: Investigate the molecular mechanisms of acid-sensing in the olfactory system. Acidic environments have played a significant role in influencing critical survival behaviors include food discrimination, predator avoidance, and host-seeking in different animals. To understand the molecular mechanisms of acid-sensing in the olfactory system and if acid environment affects normal olfaction, I used type III adenylyl cyclase (AC3) KO mice, which lose the sense of smell, to investigate the mechanism of sensing volatile acidic compounds in olfactory neurons. Previously work has shown that AC3 KO mice retain the ability to sense acids in the environment. Acid-sensing ion channels (ASICs) in the olfactory system are a potential candidate for mediating detection of acidic compounds. I first demonstrated that ASIC1 proteins are abundantly expressed in olfactory sensory neurons (OSNs). In addition, mRNA of other ASICs subtypes has been detected in the main olfactory epithelia (MOE). Moreover, I designed a behavioral experiment to demonstrate that acid volatiles can interfere the discrimination ability of the mouse olfactory system. Hence, this study provides the first evidence suggesting that ASICs mediate acid-sensing in OSNs. Project 2: Elucidate the roles of neuronal primary cilia in regulating principal neuron positioning during postnatal development. The cerebral cortex was chosen to study the roles of primary cilia in the central nervous system, because the mutations of cilia-related genes commonly cause microcephaly and macrocephaly in the cerebral cortex of several species, including humans. I demonstrated primary cilia of early- and late-born hippocampal neurons exhibit opposite orientations, whereas cilia of early- and late-born neocortical neurons generally point towards the pia surface. I also discovered a non-conventional “reverse migration” of late-born hippocampal cornu ammonis area 1 (CA1) and neocortical principal neurons for cell positioning in the first few weeks after birth. I also found that neuronal primary cilia serve as a "compass" that indicates the direction of reverse migration and positioning of principal neurons in the hippocampal CA1 and dentate gyrus (DG). Ablation of primary cilia in the late embryonic stage leads to cortical gyrification specifically in the cingulate and retrosplenial cortex and megalencephaly, both of which manifest primarily in the early postnatal stage. Finally, I observed that the orientation of primary cilia regulates the precise postnatal positioning of principal neurons in the hippocampal CA1 and DG. Project 3: Investigate the developmental pattern of primary cilia in the mouse adrenal glands. To date, little is known about the function of primary cilia in the peripheral nervous system. Studies suggest that primary cilia are involved in steroid hormone secretion and cell differentiation within the adrenal glands. However, research on primary cilia in the adrenal glands, such as cilia expression patterns, has not yet been conducted. I utilized an immunostaining approach to examine the expression pattern of primary cilia in the developing adrenal glands, especially during postnatal development. I found that there is a high level of expression of primary cilia in the adrenal cortex and capsule during the early postnatal period. Notably, primary cilia in adrenal chromaffin cells, which migrate in groups, exhibit irregular orientations, while primary cilia in adrenal capsule cells, which migrate as isolated cells, demonstrate a distinct opposite pattern. Collectively, my results support the idea that primary cilia are implicated in early postnatal development of adrenal glands, have a more important role in guiding the postnatal positioning of cells migrating individually than those migrating in groups

Download

Share

COinS