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GDP-bound Galphai2 regulates spinal motor neuron differentiation through interaction with GDE2.

ABSTRACT: Galphai proteins play major roles in the developing and mature nervous system, ranging from the control of cellular proliferation to modulating synaptic plasticity. Although best known for transducing signals from activated seven transmembrane G-protein coupled receptors (GPCRs) when bound to GTP, key cellular functions for Galphai-GDP are beginning to emerge. Here, we show that Galphai2 is expressed in motor neuron progenitors that are differentiating to form postmitotic motor neurons in the developing spinal cord. Ablation of Galphai2 causes deficits in motor neuron generation but no changes in motor neuron progenitor patterning or specification, consistent with a function for Galphai2 in regulating motor neuron differentiation. We show that Galphai2 function is mediated in part by its interaction with GDE2, a known regulator of motor neuron differentiation, and that disruption of the GDE2/Galphai2 complex in vivo causes motor neuron deficits analogous to Galphai2 ablation. Galphai2 preferentially associates with GDE2 when bound to GDP, invoking GPCR-independent functions for Galphai2 in the control of spinal motor neuron differentiation.

SUBMITTER: Periz G

PROVIDER: S-EPMC2854168 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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GDP-bound Galphai2 regulates spinal motor neuron differentiation through interaction with GDE2.

Periz Goran G Yan Ye Y Bitzer Zachary T ZT Sockanathan Shanthini S

Developmental biology 20100301 1

Galphai proteins play major roles in the developing and mature nervous system, ranging from the control of cellular proliferation to modulating synaptic plasticity. Although best known for transducing signals from activated seven transmembrane G-protein coupled receptors (GPCRs) when bound to GTP, key cellular functions for Galphai-GDP are beginning to emerge. Here, we show that Galphai2 is expressed in motor neuron progenitors that are differentiating to form postmitotic motor neurons in the de ...[more]

PMID: 20197066

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Project description:The motor neuron (MN)–hexamer complex consisting of LIM homeobox 3, Islet-1, and nuclear LIM interactor is a key determinant of motor neuron specification and differentiation. To gain insights into the transcriptional network in motor neuron development, we performed a genome-wide ChIP-sequencing analysis and found that the MN–hexamer directly regulates a wide array of motor neuron genes by binding to the HxRE (hexamer response element) shared among the target genes. Interestingly, STAT3-binding motif is highly enriched in the MN–hexamer–bound peaks in addition to the HxRE. We also found that a transcriptionally active form of STAT3 is expressed in embryonic motor neurons and that STAT3 associates with the MN–hexamer, enhancing the transcriptional activity of the MN–hexamer in an upstream signal-dependent manner. Correspondingly, STAT3 was needed for motor neuron differentiation in the developing spinal cord. Together, our studies uncover crucial gene regulatory mechanisms that couple MN–hexamer and STAT-activating extracellular signals to promote motor neuron differentiation in vertebrate spinal cord. To explain our experimental scheme briefly, we are interested in finding target sites for the dimer of transcription factors Isl1 and Lhx3. To mimic the biological activity of Isl1/Lhx3 dimer, we made Isl1-Lhx3 fusion and found that Isl1-Lhx3 has a potent biological activity in multiple systems (i.e. generation of ectopic motor neurons). Then we made ES cell line that induces Flag-tagged Isl1-Lhx3 expression upon Dox treatment. These *mouse* ES cells differentiate to motor neurons (iMN-ESCs) when treated with Dox following EB formation. To identify genomic binding sites of Isl1-Lhx3 (Flag-tagged), we performed ChIP with Flag antibody (pull down of Flag-Isl1-Lhx3) in ES cells treated with Dox. ChIP with Flag antibody in ES cells treated with vehicle (no Dox) was done as a negative control in parallel, and sequenced along with +Dox sample. We have done these experiments twice (two sets).

Dataset Information

GDP-bound Galphai2 regulates spinal motor neuron differentiation through interaction with GDE2.

Publications

GDP-bound Galphai2 regulates spinal motor neuron differentiation through interaction with GDE2.

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