title: ZPK/DLK and MKK4 form the critical gateway to axotomy-induced motoneuron death in neonates.
abstract: Motoneuron death after transection of the axons (axotomy) in neonates is believed to share the same mechanistic bases as naturally occurring programmed cell death during development. The c-Jun N-terminal kinase pathway is activated in both forms of motoneuron death, but it remains unknown to what extent these two forms of motoneuron death depend on this pathway and which upstream kinases are involved. We found that numbers of facial motoneurons are doubled in neonatal mice deficient in either ZPK/DLK (zipper protein kinase, also known as dual leucine zipper kinase), a mitogen-activated protein kinase kinase kinase, or in MKK4/MAP2K4, a mitogen-activated protein kinase kinase directly downstream of ZPK/DLK, and that the facial motoneurons in those mutant mice are completely resistant to axotomy-induced death. Conditional deletion of MKK4/MAP2K4 in neurons further suggested that ZPK/DLK and MKK4/MAP2K4-dependent mechanisms underlying axotomy-induced death are motoneuron autonomous. Nevertheless, quantitative analysis of facial motoneurons during embryogenesis revealed that both ZPK/DLK and MKK4/MAP2K4-dependent and -independent mechanisms contribute to developmental elimination of excess motoneurons. In contrast to MKK4/MAP2K4, mice lacking MKK7/MAP2K7, another mitogen-activated protein kinase kinase directly downstream of ZPK/DLK, conditionally in neurons did not have excess facial motoneurons. However, some MKK7/MAP2K7-deficient facial motoneurons were resistant to axotomy-induced death, indicating a synergistic effect of MKK7/MAP2K7 on axotomy-induced death of these facial motoneurons. Together, our study provides compelling evidence for the pivotal roles of the ZPK/DLK and MKK4/MAP2K4-dependent mechanism in axotomy-induced motoneuron death in neonates and also demonstrates that axotomy-induced motoneuron death is not identical to developmental motoneuron death with respect to the involvement of ZPK/DLK, MKK4/MAP2K4 and MKK7/MAP2K7.
authors.affiliation: Department of Neurology, School of Medicine and Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento, California 95817, takito@ucdavis.edu.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Department of Neurology, School of Medicine and Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento, California 95817.
authors.forename: Makoto
authors.initials: M
authors.lastname: Horiuchi
authors.affiliation: Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento, California 95817.
authors.forename: Raymond H
authors.initials: RH
authors.lastname: Ikeda
authors.affiliation: Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento, California 95817.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, California 95616, Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento, California 95817.
authors.forename: Peter
authors.initials: P
authors.lastname: Bannerman
authors.affiliation: Department of Neurology, School of Medicine and Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento, California 95817.
authors.forename: David
authors.identifier: http://orcid.org/0000-0002-9122-1268
authors.initials: D
authors.lastname: Pleasure
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Science, 1030 Vienna, Austria, and.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Cathy
authors.initials: C
authors.lastname: Tournier
authors.affiliation: Department of Neurology, School of Medicine and Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento, California 95817.
authors.forename: Aki
authors.initials: A
authors.lastname: Itoh
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019771:Axotomy / Q000009:adverse effects; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002490:Central Nervous System / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003911:Dextrans; D004195:Disease Models, Animal; D020220:Facial Nerve Injuries / Q000378:metabolism / Q000473:pathology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012235:Rhodamines; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D003911:Dextrans; C067661:Fluoro-Ruby; D008840:Microfilament Proteins; D064231:Nestin; D016755:Proto-Oncogene Proteins c-jun; D012235:Rhodamines; D002795:Choline O-Acetyltransferase; D020930:MAP Kinase Kinase Kinases; C090757:mitogen-activated protein kinase kinase kinase 12; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D010751:Phosphopyruvate Hydratase
keywords: injury response; mitogen-activated protein kinase; programmed cell death
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