Close Homolog of L1 Regulates Dendritic Spine Density in the Mouse Cerebral Cortex Through Semaphorin 3B

J Neurosci. 2019 Aug 7;39(32):6233-6250. doi: 10.1523/JNEUROSCI.2984-18.2019. Epub 2019 Jun 10.


Dendritic spines in the developing mammalian neocortex are initially overproduced and then eliminated during adolescence to achieve appropriate levels of excitation in mature networks. We show here that the L1 family cell adhesion molecule Close Homolog of L1 (CHL1) and secreted repellent ligand Semaphorin 3B (Sema3B) function together to induce dendritic spine pruning in developing cortical pyramidal neurons. Loss of CHL1 in null mutant mice in both genders resulted in increased spine density and a greater proportion of immature spines on apical dendrites in the prefrontal and visual cortex. Electron microscopy showed that excitatory spine synapses with postsynaptic densities were increased in the CHL1-null cortex, and electrophysiological recording in prefrontal slices from mutant mice revealed deficiencies in excitatory synaptic transmission. Mechanistically, Sema3B protein induced elimination of spines on apical dendrites of cortical neurons cultured from wild-type but not CHL1-null embryos. Sema3B was secreted by the cortical neuron cultures, and its levels increased when cells were treated with the GABA antagonist gabazine. In vivo CHL1 was coexpressed with Sema3B in pyramidal neuron subpopulations and formed a complex with Sema3B receptor subunits Neuropilin-2 and PlexinA4. CHL1 and NrCAM, a closely related L1 adhesion molecule, localized primarily to distinct spines and promoted spine elimination to Sema3B or Sema3F, respectively. These results support a new concept in which selective spine elimination is achieved through different secreted semaphorins and L1 family adhesion molecules to sculpt functional neural circuits during postnatal maturation.SIGNIFICANCE STATEMENT Dendritic spines in the mammalian neocortex are initially overproduced and then pruned in adolescent life through unclear mechanisms to sculpt maturing cortical circuits. Here, we show that spine and excitatory synapse density of pyramidal neurons in the developing neocortex is regulated by the L1 adhesion molecule, Close Homolog of L1 (CHL1). CHL1 mediated spine pruning in response to the secreted repellent ligand Semaphorin 3B and associated with receptor subunits Neuropilin-2 and PlexinA4. CHL1 and related L1 adhesion molecule NrCAM localized to distinct spines, and promoted spine elimination to Semaphorin 3B and -3F, respectively. These results support a new concept in which selective elimination of individual spines and nascent synapses can be achieved through the action of distinct secreted semaphorins and L1 adhesion molecules.

Keywords: Semaphorin 3B; autism spectrum disorders; cell adhesion molecule; close homolog of L1; dendritic spine; spine pruning.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology
  • Animals
  • Cell Adhesion Molecules / deficiency
  • Cell Adhesion Molecules / physiology*
  • Cells, Cultured
  • Dendritic Spines / physiology*
  • Female
  • GABA Agonists / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins / physiology
  • Neuropilin-2 / physiology
  • Patch-Clamp Techniques
  • Prefrontal Cortex / cytology
  • Prefrontal Cortex / growth & development
  • Prefrontal Cortex / physiology*
  • Protein Interaction Mapping
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / physiology
  • Pyramidal Cells / ultrastructure
  • Pyridazines / pharmacology
  • Receptors, Cell Surface / physiology
  • Semaphorins / physiology*
  • Synaptic Transmission
  • Visual Cortex / cytology
  • Visual Cortex / growth & development
  • Visual Cortex / physiology*


  • Cell Adhesion Molecules
  • Chl1 protein, mouse
  • GABA Agonists
  • Nerve Tissue Proteins
  • Neuropilin-2
  • Nrcam protein, mouse
  • Plxna4 protein, mouse
  • Pyridazines
  • Receptors, Cell Surface
  • Sema3b protein, mouse
  • Semaphorins
  • gabazine