PAF-AH Catalytic Subunits Modulate the Wnt Pathway in Developing GABAergic Neurons
Idit Livnat1, Danit Finkelshtein, Indraneel Ghosh
1Department of Molecular Genetics, Weizmann Institute of Science Rehovot, Israel.
Frontiers in Cellular Neuroscience
|August 21, 2010
Summary
Platelet-activating factor acetylhydrolase 1B (PAF-AH) catalytic subunits regulate brain development by negatively modulating Wnt signaling. Their absence increases GABAergic neuron proliferation and alters interneuron migration in the developing cerebral cortex.
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Platelet-activating factor acetylhydrolase 1B (PAF-AH) enzyme regulates the phospholipid platelet-activating factor (PAF).
- The roles of PAF-AH catalytic subunits (alpha1 and alpha2) in brain development are largely unknown.
- PAF-AH is composed of catalytic subunits and a regulatory subunit, LIS1.
Purpose of the Study:
- To investigate the function of PAF-AH catalytic subunits in the developing brain.
- To examine their effects on GABAergic neuron proliferation and interneuron migration.
- To elucidate their role in Wnt signaling pathways during cortical development.
Main Methods:
- Utilized knockout mice lacking alpha1 and alpha2 catalytic subunits.
- Performed overexpression studies of PAF-AH catalytic subunits.
- Employed in situ hybridization to analyze gene expression.
- Conducted transplantation assays to assess cell migration.
Main Results:
- Absence of PAF-AH catalytic subunits led to increased ganglionic eminence size due to enhanced GABAergic neuron proliferation.
- PAF-AH catalytic subunits negatively regulate Wnt signaling, reducing nuclear beta-catenin.
- Wnt signaling components and downstream targets (Cyclin D1, Tcf4, Tcf3, Wnt7B) were upregulated in mutant mice.
- Interneuron number and migration were advanced in the cerebral cortex, partly due to Sdf1 and Netrin-1 upregulation.
Conclusions:
- PAF-AH catalytic subunits act as negative regulators of Wnt signaling in specific regions of the developing cerebral cortex.
- These subunits influence GABAergic neuron proliferation and interneuron migration.
- Modulation of Wnt signaling is a conserved function of PAF-AH catalytic subunits in brain development.
More Related Videos
07:34The Power of Simplicity: Sea Urchin Embryos as in Vivo Developmental Models for Studying Complex Cell-to-cell Signaling Network Interactions
Published on: February 16, 2017
09:07Genetic Manipulation of Cerebellar Granule Neurons In Vitro and In Vivo to Study Neuronal Morphology and Migration
Published on: March 17, 2014
Related Concept Videos
01:41Non-Canonical Wnt Signaling Pathways
Wnt is a zygotic effect gene that is expressed during very early embryonic development. It regulates various processes in animals starting from early development through the adult stage, such as organogenesis in the embryo and maintenance of neuronal and blood stem cells. Wnt proteins can induce a wide variety of intracellular pathways depending upon the specific abilities of different Wnt ligands to form a complex with shared and cognate receptors in the presence of different co-receptors. The...
01:41Non-Canonical Wnt Signaling Pathways
Wnt is a zygotic effect gene that is expressed during very early embryonic development. It regulates various processes in animals starting from early development through the adult stage, such as organogenesis in the embryo and maintenance of neuronal and blood stem cells. Wnt proteins can induce a wide variety of intracellular pathways depending upon the specific abilities of different Wnt ligands to form a complex with shared and cognate receptors in the presence of different co-receptors. The...
02:54Canonical Wnt Signaling Pathway
The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which results in tumor...
02:54Canonical Wnt Signaling Pathway
The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which results in tumor...
01:09GPCRs Regulate Adenylyl Cylase Activity
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
Two...
01:22Activation and Inactivation of G Proteins
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...