Genetic analysis of Mint/X11 proteins: essential presynaptic functions of a neuronal adaptor protein family.
Mints/X11s are adaptor proteins composed of three isoforms: neuron-specific Mints 1 and 2, and the ubiquitously expressed Mint 3. We have now analyzed constitutive and conditional knock-out mice for all three Mints/X11s. We found that approximately 80% of mice lacking both neuron-specific Mint isoforms (Mints 1 and 2) die at birth, whereas mice lacking any other combination of Mint isoforms survive normally. The approximately 20% surviving Mint 1/2 double knock-out mice exhibit a decrease in weight and deficits in motor behaviors. Hippocampal slice electrophysiology uncovered a decline in spontaneous neurotransmitter release, lowered synaptic strength, and enhanced paired-pulse facilitation in Mint-deficient mice, suggesting a decreased presynaptic release probability. Acute ablation of Mint expression in cultured neurons from conditional Mint 1/2/3 triple knock-in mice also revealed a decline in spontaneous release, confirming that deletion of Mints impair presynaptic function. Quantitation of synaptic proteins showed that acute deletion of Mints caused a selective increase in Munc18-1 and Fe65 proteins, and overexpression of Munc18-1 in wild-type neurons also produced a decrease in spontaneous release, suggesting that the interaction of Mints with Munc18-1 may contribute to the presynaptic phenotype observed in Mint-deficient mice. Our studies thus indicate that Mints are important regulators of presynaptic neurotransmitter release that are essential for mouse survival.
Ho
Angela
A
Center for Basic Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111,USA. angela.ho@utsouthwestern.edu
Morishita
Wade
W
Atasoy
Deniz
D
Liu
Xinran
X
Tabuchi
Katsuhiko
K
Hammer
Robert E
RE
Malenka
Robert C
RC
Südhof
Thomas C
TC
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D033942:Adaptor Proteins, Vesicular Transport / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D006624:Hippocampus / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D017729:Presynaptic Terminals / Q000378:metabolism / Q000502:physiology*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D009435:Synaptic Transmission / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C513072:Apba1 protein, mouse; C485530:Apba3 protein, mouse; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011506:Proteins; D016601:RNA-Binding Proteins; C121253:Spen protein, mouse