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Regulation of synapse density by Pumilio RNA-binding proteins.

Lisa K Randolph1, Michaela M Pauers1, José C Martínez2

  • 1Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY 10032, USA.

Cell Reports
|September 19, 2024
PubMed
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Downregulating Pumilio proteins enhances synapse density and maturation in neurons. This suggests Pumilio proteins are key regulators of synaptic development and stabilization.

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CP: Molecular biologyCP: NeurosciencePumilioRNA-binding proteinslocal translationmRNA regulationsynapse

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Developmental Biology

Background:

  • Synapse formation, stabilization, and elimination are critical processes in neural development and adult brain function.
  • Pumilio RNA-binding proteins (Pum1, Pum2) are known to regulate mRNA translation and localization, impacting synaptic function.
  • Pumilio proteins are developmentally downregulated in the brain.

Purpose of the Study:

  • To investigate the role of Pumilio 1 and 2 downregulation in synaptic development.
  • To determine the impact of Pumilio loss on synapse density, maturation, and associated molecular pathways.

Main Methods:

  • Primary hippocampal neuron culture.
  • Analysis of excitatory and inhibitory synapse density.
  • Assessment of synapse maturation markers.
  • RNA sequencing to identify changes in mRNA expression in the mouse brain following Pum1 and Pum2 loss.

Main Results:

  • Simultaneous downregulation of Pumilio 1 and 2 significantly increased both excitatory and inhibitory synapse density in primary hippocampal neurons.
  • Loss of Pum1 and Pum2 promoted synapse maturation.
  • In the mouse brain, loss of Pum1 and Pum2 was linked to increased mRNAs involved in mitochondrial function and synaptic translation.

Conclusions:

  • Developmental downregulation of Pumilio proteins is a crucial permissive step for synapse maturation.
  • Modulating Pumilio levels represents a cell-intrinsic mechanism for neurons to regulate their capacity for synapse stabilization.
  • Pumilio proteins are key regulators of synaptic plasticity and neural development.