The Role of Arrestins in Development - Progress in Molecular Biology and Translational Science - page 222

loss of Gprk2, the Drosophila homolog of vertebrate GRKs 4-6, with ectopic
expression of kurtz exacerbates the Hh phenotype. 24
In keeping with its inhibitory roles in signal transduction during fly
development, kurtz has also been reported to attenuate Notch signaling. 28
It has been suggested that kurtz forms a complex with Notch and Deltex,
which induces ubiquitination and degradation of Notch. 28 Although these
examples substantiate the complexity of arr function, they also underline

the importance of further studies to fully define the functional differences
as well as overlaps of

b

b arrs in flies and vertebrates.

4. b -ARRESTINS IN VERTEBRATE DEVELOPMENT
4.1. b arr1 in hematopoiesis
Despite the common characteristic of b arrs to act as scaffolding proteins in
receptor signaling, arr1 and 2 also have distinct functions. This becomes

very apparent during embryonic development. Experiments in zebrafish
using a morpholino (MO)-based knockdown strategy revealed an unantic-
ipated role for

b

arr2. 19 Depletion of arr1 protein in

zebrafish embryos selectively interferes with early hematopoiesis. This is
especially interesting, as

b arr1, but not for b b

arr1 appears to be uniformly expressed in the early
embryo and not just in hematopoietic lineages. 19 Knockdown of

b

b arr1, but

not arr2, markedly decreases the expression of genes that are essential for

blood development, such as gata1 and scl ( stem cell leukemia hematopoietic
transcription factor ). 29,30 Hh target genes on the other hand, for which expres-
sion depends on

b

arr2, 18 are unchanged when b b arr1 is lost. Microarray anal-

ysis revealed that arr1 depletion is reflected in the reduction of cdx4 and

certain hox genes that are associated with blood development. 31 Coinjection
of

b

arr1 MO and mRNA encoding cdx4 , hox4a ,or hox9a could in turn
rescue the

b

arr1 knockdown phenotype.
Subsequent yeast-2-hybrid experiments uncovered that

b

arr1 interacts
with Yin Yang 1 (YY1), a protein that was originally identified as a human
GLI-Kr¨ppel-related zinc finger protein and thought to act as a transcrip-
tional repressor. 32 However, as it turns out, YY1 is able to modulate tran-
scription in different ways. Depending on the respective context, YY1 can
function as a repressor, 32 as an activator, 33 or as a recruitment factor for other
proteins such as Polycomb repressors, modulating transcriptional activity. 34
In addition, binding of YY1 to certain DNA sequences may result in disrup-
tion of binding sites for other DNA-interacting molecules and can even
change the conformation of DNA. 35

b

Interestingly, hox gene expression is