Model
Digital Document
Publisher
Florida Atlantic University
Description
L1-type cell adhesion molecule (L1CAM) plays an essential role in the
development of nervous system and is also highly relevant for the progression of diseases
such as Alzheimer’s disease, stroke and cancers, some of the leading causes of human
mortality. In addition to its canonical role as a plasma membrane protein organizing the
cytoskeleton, recent in vitro studies have revealed that transmembrane as well as cytosolic
fragments of proteolytically cleaved vertebrate L1CAM translocate to the nucleus and
regulate expression of genes involved in DNA post-replication repair, cell cycle control,
migration and differentiation. However, little is known about the in vivo function of
L1CAM in the adult nervous system.
This dissertation research focuses on studying in vivo nuclear translocation and
function of L1CAM. Using the Drosophila model system, we first show that the sole
Drosophila L1CAM homolog, Neuroglian (Nrg), is proteolytically cleaved by Alzheimer’s
associated secretases, similar to L1CAM, and is also translocated to the nucleus in the adult nervous system. Subsequently, we have shown that the deletion of highly conserved
Ankyrin binding domain or FIGQY motif disrupts nuclear import. Further experiments
have revealed that the nuclear translocation of Nrg is in fact regulated by the
phosphorylation of the FIGQY motif. Importantly, our studies also show transgenic
expression of full-length Nrg or the intracellular domain of Nrg resulted in increased myc
expression, which is associated with increased sensitivity to oxidative stress and reduced
life span. On the other hand, deletion of the FIGQY motif or mutations preventing its
phosphorylation led to decrease in myc expression. In summary, we have identified a novel
role for the highly conserved Ankyrin binding domain in nuclear translocation and
transcriptional regulation of the Drosophila myc oncogene, which is of high relevance to
neurodegenerative diseases and cancer associated with oxidative stress.
development of nervous system and is also highly relevant for the progression of diseases
such as Alzheimer’s disease, stroke and cancers, some of the leading causes of human
mortality. In addition to its canonical role as a plasma membrane protein organizing the
cytoskeleton, recent in vitro studies have revealed that transmembrane as well as cytosolic
fragments of proteolytically cleaved vertebrate L1CAM translocate to the nucleus and
regulate expression of genes involved in DNA post-replication repair, cell cycle control,
migration and differentiation. However, little is known about the in vivo function of
L1CAM in the adult nervous system.
This dissertation research focuses on studying in vivo nuclear translocation and
function of L1CAM. Using the Drosophila model system, we first show that the sole
Drosophila L1CAM homolog, Neuroglian (Nrg), is proteolytically cleaved by Alzheimer’s
associated secretases, similar to L1CAM, and is also translocated to the nucleus in the adult nervous system. Subsequently, we have shown that the deletion of highly conserved
Ankyrin binding domain or FIGQY motif disrupts nuclear import. Further experiments
have revealed that the nuclear translocation of Nrg is in fact regulated by the
phosphorylation of the FIGQY motif. Importantly, our studies also show transgenic
expression of full-length Nrg or the intracellular domain of Nrg resulted in increased myc
expression, which is associated with increased sensitivity to oxidative stress and reduced
life span. On the other hand, deletion of the FIGQY motif or mutations preventing its
phosphorylation led to decrease in myc expression. In summary, we have identified a novel
role for the highly conserved Ankyrin binding domain in nuclear translocation and
transcriptional regulation of the Drosophila myc oncogene, which is of high relevance to
neurodegenerative diseases and cancer associated with oxidative stress.
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