Deletion of CASK in mice is lethal and impairs synaptic function

Deniz Atasoy, Susanne Schoch, Angela Ho, Krisztina A. Nadasy, Xinran Liu, Weiqi Zhang, Konark Mukherjee, Elena D. Nosyreva, Rafael Fernandez-Chacon, Markus Missler, Ege T. Kavalali, Thomas C. Südhof

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

CASK is an evolutionary conserved multidomain protein composed of an N-terminal Ca2+/calmodulin-kinase domain, central PDZ and SH3 domains, and a C-terminal guanylate kinase domain. Many potential activities for CASK have been suggested, including functions in scaffolding the synapse, in organizing ion channels, and in regulating neuronal gene transcription. To better define the physiological importance of CASK, we have now analyzed CASK "knockdown" mice in which CASK expression was suppressed by ≈70%, and CASK knockout (KO) mice, in which CASK expression was abolished. CASK knockdown mice are viable but smaller than WT mice, whereas CASK KO mice die at first day after birth. CASK KO mice exhibit no major developmental abnormalities apart from a partially penetrant cleft palate syndrome. In CASK-deficient neurons, the levels of the CASK-interacting proteins Mints, Veli/ Mais, and neurexins are decreased, whereas the level of neuroligin 1 (which binds to neurexins that in turn bind to CASK) is increased. Neurons lacking CASK display overall normal electrical properties and form ultrastructurally normal synapses. However, glutamatergic spontaneous synaptic release events are increased, and GABAergic synaptic release events are decreased in CASK-deficient neurons. In contrast to spontaneous neurotransmitter release, evoked release exhibited no major changes. Our data suggest that CASK, the only member of the membrane-associated guanylate kinase protein family that contains a Ca 2+/calmodulin-dependent kinase domain, is required for mouse survival and performs a selectively essential function without being in itself required for core activities of neurons, such as membrane excitability, Ca 2+-triggered presynaptic release, or postsynaptic receptor functions.

Original languageEnglish (US)
Pages (from-to)2525-2530
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number7
DOIs
StatePublished - Feb 13 2007

Fingerprint

Guanylate Kinases
Knockout Mice
Neurons
Calcium-Calmodulin-Dependent Protein Kinases
Synapses
Mentha
PDZ Domains
Proteins
src Homology Domains
Cleft Palate
Ion Channels
Neurotransmitter Agents
Parturition
Membranes
Genes

Keywords

  • CaM kinase
  • MAGUK
  • Neurexin
  • Neurotransmitter release
  • Synapse

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Deletion of CASK in mice is lethal and impairs synaptic function. / Atasoy, Deniz; Schoch, Susanne; Ho, Angela; Nadasy, Krisztina A.; Liu, Xinran; Zhang, Weiqi; Mukherjee, Konark; Nosyreva, Elena D.; Fernandez-Chacon, Rafael; Missler, Markus; Kavalali, Ege T.; Südhof, Thomas C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 7, 13.02.2007, p. 2525-2530.

Research output: Contribution to journalArticle

Atasoy, D, Schoch, S, Ho, A, Nadasy, KA, Liu, X, Zhang, W, Mukherjee, K, Nosyreva, ED, Fernandez-Chacon, R, Missler, M, Kavalali, ET & Südhof, TC 2007, 'Deletion of CASK in mice is lethal and impairs synaptic function', Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 7, pp. 2525-2530. https://doi.org/10.1073/pnas.0611003104
Atasoy, Deniz ; Schoch, Susanne ; Ho, Angela ; Nadasy, Krisztina A. ; Liu, Xinran ; Zhang, Weiqi ; Mukherjee, Konark ; Nosyreva, Elena D. ; Fernandez-Chacon, Rafael ; Missler, Markus ; Kavalali, Ege T. ; Südhof, Thomas C. / Deletion of CASK in mice is lethal and impairs synaptic function. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 7. pp. 2525-2530.
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AU - Ho, Angela

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AU - Liu, Xinran

AU - Zhang, Weiqi

AU - Mukherjee, Konark

AU - Nosyreva, Elena D.

AU - Fernandez-Chacon, Rafael

AU - Missler, Markus

AU - Kavalali, Ege T.

AU - Südhof, Thomas C.

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