Date of Award

Winter 12-15-2017

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Biochemistry)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

The essential element zinc plays an important structural and functional role in proteins in

all living organisms. Zinc homeostasis is critical, because both zinc deficiency and excess are

deleterious; in humans, defective zinc homeostasis leads to several disease states. The

mechanisms utilized by animals to respond to excess zinc have been extensively characterized,

but much less is known about how animals sense and respond to zinc deficiency. A primary

method animals use to increase zinc content is through the zinc transport family known as the

Zrt, Irt-like proteins (ZIPs). Caenorhabditis elegans is a powerful experimental system to study

the mechanisms of zinc deficiency based on sophisticated genetic and cell biological approaches,

and studies of C. elegans are likely to be relevant to humans, since both worms and humans have

14 ZIP family members.

To characterize the mechanisms that animals use to respond to zinc deficiency, we

examined the transcriptional response of the ZIP family members during zinc deficient

conditions. We demonstrated that three ZIP genes in C. elegans, zipt-2.1, zipt-2.3, and zipt-7.1,

are upregulated in zinc deficient conditions. The promoters of these genes contained a conservedcis-regulatory element we have named the low zinc activating (LZA) element. This element was

necessary and sufficient to drive transcriptional activation in zinc deficient conditions. We also

bioinformatically identified candidate genes that contained an LZA within their promoters and

demonstrated that these genes are also activated by zinc deficient conditions. To understand the

conservation of the function of the LZA, we transfected the promoter of zipt-2.3 into human cells

and determined that the promoter was activated in zinc deficient conditions and this activation

was dependent on the LZA element. These efforts elucidated the mechanisms that animals use to

respond to zinc deficiency, including the discovery of a novel, conserved cis-regulatory element.

Another mechanism used by animals to respond to changes in zinc availability is through the

function of zinc transport proteins. We identified the C. elegans ZIP family member zipt-2.3 as a

gene that was essential for growth and development during zinc deficiency. ZIPT-2.3 was

expressed within lysosome-related organelles known as gut granules within the C. elegans

intestine. This ZIP mediates the mobilization of zinc from these storage sites to allow animals to

maintain proper zinc homeostasis. These results demonstrated that zinc storage and its

subsequent mobilization from intracellular storage sites are the major mechanisms these animals

use to adapt to changes in zinc status, and these mechanisms have been suggested to play crucial

roles in other organisms.

Language

English (en)

Chair and Committee

Kerry Kornfeld

Committee Members

Jeffrey Henderson, Michael Nonet, Tim Schedl, Robert Mercer,

Comments

Permanent URL: https://doi.org/10.7936/K7C53K84

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