The Role of Arrestins in Development - Progress in Molecular Biology and Translational Science - page 229

b

of Gli. For example, arr2 is localized to the primary cilium of MEFs derived

from wild-type mice and its absence in MEFs derived from

arr2 KO mice
has been reported to cause uncontrolled cell proliferation and defects in
ciliogenesis. 83 Whether this effect is regulated by Smo has not been exam-
ined in detail, and thus, the mechanism of this putative role of

b

arr2 is not
clear yet. It could potentially involve the scaffolding of molecules that are
necessary for cell cycle regulation.

b

4.3.2 b arr1 in Hh signaling
At the time the role of arr2 in the Hh pathway was revealed in zebrafish,

there was no information regarding the zebrafish homolog of

b

b arr1. There-

arr1 in Hh signaling was not studied at the time. 18
Five years later, however, Yue et al. 19 published a study on zebrafish

b

fore, a potential role for

arr1
and its developmental phenotypes. In this study, b arr1 depletion attenuated
hematopoiesis but did not affect the expression of Hh target genes as mea-
sured by in situ hybridization. These findings suggest that

b

arr2
might play distinct roles during embryonic development. However, an
influence of

b arr1 and b

arr1 depletion on Hh signaling cannot be fully ruled out
because in situ hybridization may not be sensitive enough to detect mild
changes in gene expression and other measures were not explored.
Despite the results reported by Yue et al. an interesting but negative role
in Shh-mediated cell proliferation has recently been uncovered for

b

arr1 in
mammalian neuronal development. 84 As previously shown, b arr1 translo-
cates to the nucleus of transfected fibroblasts in response to opioid receptor
activation. 37 In the nucleus,

b

arr1 is enriched at specific promoters, such as
that of the cyclin-dependent kinase (CDK) inhibitor p27 and c-fos . Conse-
quently,

b

arr1 facilitates the recruitment of histone acetyltransferase p300,
resulting in local chromatin reorganization and transcription of these
genes. 37 To date, no apparent phenotype that could be explained by defects
in cell cycle control has been reported for

b

b arr1 KO mice, suggesting that

the role of arr1 on gene expression in vivo is either limited or compensated.

However, a potential physiological role for

b

b

arr1 may still exist in cell cycle
regulation as reported by Parathath et al. 84 In this study, ex vivo Shh stimu-
lation of cerebellar granule neuron precursors (CGNPs) isolated from post-
natal day 5 (P5) mice upregulated b arr1, but not b arr2, levels and facilitated

arr1 translocation to the nucleus of these developing cells. 84 There, b arr1

interacts with P300 and the transcription factor CREB selectively at the pro-
moter of the p27 gene, causing enhanced p27 transcription. This Shh-
mediated transcription is accompanied by reduced cell proliferation and

b