Download ABERRANT RECEPTOR TYROSINE KINASE SIGNALLING IN

ABERRANT RECEPTOR TYROSINE KINASE SIGNALLING IN UROFACIAL
SYNDROME
INTRODUCTION: Urofacial syndrome (UFS) is an autosomal recessive disease
characterised by congenital urinary bladder dyssynergia, ascending urosepsis and renal
failure. We identified null mutations in HPSE2 in some UFS families, and our research on
HPSE2 in embryonic frogs uncovered a role for this gene in growth factor / receptor tyrosine
kinase (RTK) signalling and peripheral nerve development. More recently, we found LRIG2
mutations in UFS families that lacked HPSE2 mutations. Nevertheless, the aberrant cell
biology and biochemistry that underlies UFS in mammals is not understood. Accordingly, we
set out to localise Lrig2 in developing mice and study growth factor signalling in the bladders
of mice with homozygous targeted Lrig2 null mutations.
METHODS: Tissues were studied by immunohistochemistry. In addition, bladder proteins
were analysed with RTK arrays. Chemiluminescent images were captured on a ChemicDoc
and quantified using ImageStudio software.
RESULTS: At embryonic day 11 (anatomically equivalent to a six week human embryo),
Lrig2 immunolocalised to the lateral neural tube and to emanating motor nerves. At
embryonic day 14 (equivalent to a ten week human embryo) pelvic ganglia, which contain
parasympathetic and sympathetic motor neuronal cell bodies, immunostained for Lrig2. As
the bladder matured, Lrig2 was detected in both smooth muscle and invading autonomic
nerves. The neural pattern was maintained over the first month after birth as the bladder
functionally matures. In two week old pups, bladder emptying was significantly impaired in
Lrig2 null versus wildtype littermates. Of 28 phosphoproteins detected in bladders of these
mice, marked reductions were observed for ErbB2 and Axl in mutant bladders. Notably,
ErbB2 has been implicated in both somatic and autonomic nerve development and Axl in
neuronal growth.
CONCLUSION: Collectively, these results support the hypothesis that Lrig2 is required for
urinary tract neuronal differentiation. Moreover, this is the first description of a faithful
animal model for the bladder disease seen in people with LRIG2 mutations. Altered RTK
signalling may underlie the neuronal defect. Further research will help to inform clinical
interventions and target research for novel therapies of UFS and similar lower urinary tract
diseases.