1. Cerebellar Defects in a Mouse Model for Muscle Eye Brain
Disease
Taylor M. Hall
Under the Supervision of Dr. Susan C. Brown
With Laboratory Assistance from Jihee Kim and Vincente Pagalda-Vergara
The Royal Veterinary College
Summer Research Internship 2015

2. Abstract
Muscle Eye Brain disease (MEB) is a severe form of congenital muscular
dystrophy in which patients present with structural brain and eye abnormalities. It is
caused by mutations in fukutin-related protein (FKRP), a gene that among 18 others is
associated with a class of diseases known as “dystroglycanopathies.” The underlying
disease mechanism of these conditions is the hypoglycoslylation of α-dystroglycan,
causing a decrease it the protein’s binding affinity for extracellular ligands necessary for
the proper assemblage of basement membranes. In the past, the disruptions caused by
hypoglycosylation have been observed in the pial basement membrane of the cerebral
cortex and the inner limiting membrane (ILM) of the eye using FKRPKD (FKRP knock-
down) mice (Ackroyd et al., 2011). However, previous to this study, little was known
about the condition of the cerebellar basement membrane. Using newborn FKRPKD mice,
we examined the basement membrane of the cerebellum and found gross disruptions in
its composition and organization, despite its relatively undeveloped state at birth. Similar
to findings in the pial basement membrane, the cerebellum showed significant reductions
in the expression of laminin α2 and α5 and ectopic deposits of laminin α1beneath the
surface of the membrane. In addition, our findings suggest these defects in the basement
membrane may cause improper neuronal migration and contribute to the abnormal
cerebellar development seen in patients.
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