Description
- Abstract:
- Autism constitutes a diverse set of disorders thought to affect neuronal connectivity and circuit development. Its etiology is heterogeneous, but certain rare genetic mutations have been implicated in autism. In this thesis, I focus on endosomal Na+-H+ exchangers, NHE6 and NHE9, and their roles in the process of neuronal development. I first describe the development of unique reagents crucial to our studies, after which I utilize those reagents to answer fundamental research questions. First, where within the endosomal pathway of neurons are Nhe6 and Nhe9 localized, and how do these localization patterns relate to one another? Second, what is the effect of Nhe9 loss on endosomal pH within neurons? And third, given the contrasting results in pH measurement with Nhe6 and Nhe9 loss, what is the effect of Nhe6 and Nhe9 on the trafficking of cargo throughout the endosomal system? More specifically, Chapter 3 demonstrates that, in contrast to previous studies of mammalian cell lines, Nhe6 and Nhe9 localize to all endosomal compartments within primary hippocampal neurons. The localization patterns of Nhe6 and Nhe9 overlap to some extent; however, in large measure, their localizations are distinct. In Chapter 4, I show that loss of Nhe9 results in an increase in more alkaline endosomes in neurons, a surprising yet intriguing result, based on prior knowledge that Nhe6 loss overacidifies the endosome. I then proceed to investigate the effect of Nhe6 and Nhe9 loss on the trafficking of cargo through endosomes, as a model to explain the unexpected pH result. Data from these studies suggest that there is a back-up of cargo in more alkaline early endosomes in Nhe9-null neurons, whereas Nhe6-null neurons may represent an acceleration of cargo to more acidic late endosomes. Thus, the work described within this thesis demonstrates a distinct role for NHE9 from NHE6 in neuronal development and informs the field as to the relationship between these two proteins.
- Notes:
- Thesis (Ph.D.)--Brown University, 2017
Access Conditions
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Citation
Sciarra, Laura N.,
"A Distinct Role for Endosomal Na+-H+ Exchanger 9 (NHE9) from NHE6 in Neuronal Development"
(2017).
Neuroscience Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.7301/Z0ST7N8K
