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Vol. 15, No. 23, pp. 3217-3229, December 1, 2001
Biology Department and Center for Cancer Research, Massachusetts
Institute of Technology, Cambridge, Massachusetts 02139, USA
Mutations in the homeobox gene vHnf1 are associated with
human diseases MODY5 (maturity-onset diabetes of the young, type V) and
familial GCKD (glomerulocystic kidney disease). In an
insertional mutagenesis screen in zebrafish, we isolated mutant alleles
of vhnf1. Phenotypes of these mutants include formation of
kidney cysts, underdevelopment of the pancreas and the liver, and
reduction in size of the otic vesicles. We show that these
abnormalities arise from patterning defects during development. We
further provide evidence that vhnf1 regulates the expression of
key patterning genes for these organs. vhnf1 is required for
the proper expression of pdx1 and shh (sonic
hedgehog) in the gut endoderm, pax2 and wt1 in the
pronephric primordial, and valentino (val) in the
hindbrain. Complementary to the loss-of-function phenotypes,
overexpression of vhnf1 induces expansion of the val
expression domain in the hindbrain. We propose that vhnf1
controls development of multiple organs through regulating regional
specification of organ primordia. The similarity between
vhnf1-associated fish phenotypes and human symptoms suggests a
correlation between developmental functions of vhnf1 and the
molecular etiology of MODY5 and GCKD.
[Key Words: vhnf1; hindbrain; liver; pancreas; kidney; regional specification]
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