Making Connections: Dendrite Arborization and Synapse Formation
During brain development, billions of neurons must be precisely connected to form intricate neural circuits. Most communication between neurons in these circuits occurs via synapses that connect the axons of signal-sending neurons to the dendrites of signal-receiving neurons. The ability of a dendrite to properly receive and process this information depends on: 1) the size and complexity of its arbor, and 2) the number and molecular composition of its synapses. Importantly, defects in dendrite morphology and synapse number are found in many psychiatric disorders, including schizophrenia, bipolar disorder, depression and addiction. A key unanswered question is how dendrite growth and synapse formation are coordinated at the molecular level to achieve proper connectivity during brain development.
During our studies on Reelin signaling in migration, we identified the CUB and Sushi Multiple Domains 2 (Csmd2) protein as a novel interactor of Dab1. Surprisingly, we found that Csmd2 loss of function did not affect neuronal migration, suggesting a role in a different Dab1-dependent process. The Reelin/Dab1 pathway has recently emerged as an important control point for dendrite formation and synapse maturation. Accordingly, deficiencies in Reelin signaling have been linked to several psychiatric diseases that do no exhibit neuronal migration deficits, but are characterized by defects in dendrites and synapses. However, we still know very little about how Reelin signaling regulates dendrite outgrowth and synaptogenesis.
Csmd2 is widely expressed in the brain, but the functions of this large transmembrane proteins is largely unknown. Interestingly, Csmd2 shares similar domain architecture with known dendritic and synaptic proteins. We have discovered that Csmd2 localizes to dendrites and synapses of neocortical and hippocampal neurons, where its cytoplasmic tail interacts with several post-synaptic scaffolding proteins. We further find that disrupting Csmd2 function causes defects in dendrite outgrowth and dendritic spine number. We are now studying the potential role of Csmd2 as a critical link that connects Reelin/Dab1 signaling to dendrite development and synapse maturation.
We also collaborate with other labs that study various aspects of dendrite and synapse formation and function.
During our studies on Reelin signaling in migration, we identified the CUB and Sushi Multiple Domains 2 (Csmd2) protein as a novel interactor of Dab1. Surprisingly, we found that Csmd2 loss of function did not affect neuronal migration, suggesting a role in a different Dab1-dependent process. The Reelin/Dab1 pathway has recently emerged as an important control point for dendrite formation and synapse maturation. Accordingly, deficiencies in Reelin signaling have been linked to several psychiatric diseases that do no exhibit neuronal migration deficits, but are characterized by defects in dendrites and synapses. However, we still know very little about how Reelin signaling regulates dendrite outgrowth and synaptogenesis.
Csmd2 is widely expressed in the brain, but the functions of this large transmembrane proteins is largely unknown. Interestingly, Csmd2 shares similar domain architecture with known dendritic and synaptic proteins. We have discovered that Csmd2 localizes to dendrites and synapses of neocortical and hippocampal neurons, where its cytoplasmic tail interacts with several post-synaptic scaffolding proteins. We further find that disrupting Csmd2 function causes defects in dendrite outgrowth and dendritic spine number. We are now studying the potential role of Csmd2 as a critical link that connects Reelin/Dab1 signaling to dendrite development and synapse maturation.
We also collaborate with other labs that study various aspects of dendrite and synapse formation and function.
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eNeuro | (2019) May 8;6(2).
Csmd2 is a Synaptic Transmembrane Protein that Interacts with PSD-95 and is Required for Neuronal Maturation Gutierrez MA, Dwyer BE, Franco SJ. bioRxiv | (2020) 2020.01.30.925537 Csmd2 interacts with Dab1 and is Required in Reelin-mediated Neuronal Maturation Gutierrez MA, Dwyer BE, Franco SJ. |
Neuron | (2023) February 1;111(3):362-371.
Dually innervated dendritic spines develop in the absence of excitatory activity and resist plasticity through tonic inhibitory crosstalk. Kleinjan MS, Buchta WC, Ogelman R, Hwang IW, Kuwajima M, Hubbard DD, Kareemo DJ, Prikhodko O, Olah SL, Gomez Wulschner LE, Abraham WC, Franco SJ, Harris KM, Oh WC, Kennedy MJ. Journal of Neuroscience | (2013) Sep 25;33(39):15652-68. Dab1 is required for hippocampal synaptic plasticity and associative learning. Trotter J, Lee GH, Kazdoba T, Crowell B, Domogauer J, Mahoney H, Franco SJ, Muller U, Weeber E, D'Arcangelo G. |