4.7 Article

Tropomodulin Isoform-Specific Regulation of Dendrite Development and Synapse Formation

Journal

JOURNAL OF NEUROSCIENCE
Volume 38, Issue 48, Pages 10271-10285

Publisher

SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3325-17.2018

Keywords

actin; cytoskeleton; dendritic arborization; dendritic spines; pointed end

Categories

Funding

  1. National Institutes of Health [GM-083889, MH-104632, MH-108025, 5F31-NS-092437-03, EY-017724, EY-014852, AR-067786]
  2. Emory University Integrated Cellular Imaging Microscopy Core of the Emory Neuroscience National Institute of Neurological Disorders and Stroke Core Facilities Grant [5P30-NS-055077]
  3. NATIONAL EYE INSTITUTE [R01EY014852, R01EY017724] Funding Source: NIH RePORTER
  4. NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR067786] Funding Source: NIH RePORTER
  5. NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM132598, R01GM083889] Funding Source: NIH RePORTER
  6. NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH104632, R21MH108025] Funding Source: NIH RePORTER
  7. NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P30NS055077, F31NS092437] Funding Source: NIH RePORTER

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Neurons of the CNS elaborate highly branched dendritic arbors that host numerous dendritic spines, which serve as the postsynaptic platform for most excitatory synapses. The actin cytoskeleton plays an important role in dendrite development and spine formation, but the underlying mechanisms remain incompletely understood. Tropomodulins (Tmods) are a family of actin-binding proteins that cap the slow-growing (pointed) end of actin filaments, thereby regulating the stability, length, and architecture of complex actin networks in diverse cell types. Three members of the Tmod family, Tmod1, Tmod2, and Tmod3 are expressed in the vertebrate CNS, but their function in neuronal development is largely unknown. In this study, we present evidence that Tmod1 and Tmod2 exhibit distinct roles in regulating spine development and dendritic arborization, respectively. Using rat hippocampal tissues from both sexes, we find that Tmod1 and Tmod2 are expressed with distinct developmental profiles: Tmod2 is expressed early during hippocampal development, whereas Tmod1 expression coincides with synaptogenesis. We then show that knockdown of Tmod2, but not Tmod1, severely impairs dendritic branching. Both Tmod1 and Tmod2 are localized to a distinct subspine region where they regulate local F-actin stability. However, the knockdown of Tmod1, but not Tmod2, disrupts spine morphogenesis and impairs synapse formation. Collectively, these findings demonstrate that regulation of the actin cytoskeleton by different members of the Tmod family plays an important role in distinct aspects of dendrite and spine development.

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