TY - JOUR
T1 - Fragile X Protein is required for inhibition of insulin signaling and regulates glial-dependent neuroblast reactivation in the developing brain
AU - Callan, Matthew A.
AU - Clements, Nicole
AU - Ahrendt, Nicholas
AU - Zarnescu, Daniela C.
N1 - Funding Information:
We are grateful to Chris Doe, Kendal Broadie, Terry Orr-Weaver, and Helena Richardson for sharing reagents. We thank Ashley Boehringer for acquisition of eye images. We acknowledge the Drosophila Bloomington Stock Center, Vienna Drosophila RNAi Center and Developmental Studies Hybridoma Bank for stocks and antibodies and thank members of the Zarnescu lab for comments on the manuscript. This work was supported by the Arizona Biomedical Research Commission (ABRC, contract no. 820 ) and in part by the Department of Defense Idea Award ( W81XWH-09-1-0273 ), Jim Himelic Foundation (to DCZ) and the Undergraduate Biology Research Program funded by the Howard Hughes Medical Institute (no. 52006942 to N.C).
PY - 2012/6/26
Y1 - 2012/6/26
N2 - Fragile X syndrome (FXS) is the most common form of inherited mental disability and known cause of autism. It is caused by loss of function for the RNA binding protein FMRP, which has been demonstrated to regulate several aspects of RNA metabolism including transport, stability and translation at synapses. Recently, FMRP has been implicated in neural stem cell proliferation and differentiation both in cultured neurospheres as well as in vivo mouse and fly models of FXS. We have previously shown that FMRP deficient Drosophila neuroblasts upregulate Cyclin E, prematurely exit quiescence, and overproliferate to generate on average 16% more neurons. Here we further investigate FMRP's role during early development using the Drosophila larval brain as a model. Using tissue specific RNAi we find that FMRP is required sequentially, first in neuroblasts and then in glia, to regulate exit from quiescence as measured by Cyclin E expression in the brain. Furthermore, we tested the hypothesis that FMRP controls brain development by regulating the insulin signaling pathway, which has been recently shown to regulate neuroblast exit from quiescence. Our data indicate that phosphoAkt, a readout of insulin signaling, is upregulated in dFmr1 brains at the time when FMRP is required in glia for neuroblast reactivation. In addition, dFmr1 interacts genetically with dFoxO, a transcriptional regulator of insulin signaling. Our results provide the first evidence that FMRP is required in vivo, in glia for neuroblast reactivation and suggest that it may do so by regulating the output of the insulin signaling pathway. This article is part of a Special Issue entitled: RNA-Binding Proteins.
AB - Fragile X syndrome (FXS) is the most common form of inherited mental disability and known cause of autism. It is caused by loss of function for the RNA binding protein FMRP, which has been demonstrated to regulate several aspects of RNA metabolism including transport, stability and translation at synapses. Recently, FMRP has been implicated in neural stem cell proliferation and differentiation both in cultured neurospheres as well as in vivo mouse and fly models of FXS. We have previously shown that FMRP deficient Drosophila neuroblasts upregulate Cyclin E, prematurely exit quiescence, and overproliferate to generate on average 16% more neurons. Here we further investigate FMRP's role during early development using the Drosophila larval brain as a model. Using tissue specific RNAi we find that FMRP is required sequentially, first in neuroblasts and then in glia, to regulate exit from quiescence as measured by Cyclin E expression in the brain. Furthermore, we tested the hypothesis that FMRP controls brain development by regulating the insulin signaling pathway, which has been recently shown to regulate neuroblast exit from quiescence. Our data indicate that phosphoAkt, a readout of insulin signaling, is upregulated in dFmr1 brains at the time when FMRP is required in glia for neuroblast reactivation. In addition, dFmr1 interacts genetically with dFoxO, a transcriptional regulator of insulin signaling. Our results provide the first evidence that FMRP is required in vivo, in glia for neuroblast reactivation and suggest that it may do so by regulating the output of the insulin signaling pathway. This article is part of a Special Issue entitled: RNA-Binding Proteins.
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U2 - 10.1016/j.brainres.2012.03.042
DO - 10.1016/j.brainres.2012.03.042
M3 - Article
C2 - 22513101
AN - SCOPUS:84862124493
SN - 0006-8993
VL - 1462
SP - 151
EP - 161
JO - Brain research
JF - Brain research
ER -