Dentate Gyrus Development Requires ERK Activity to Maintain Progenitor Population and MAPK Pathway Feedback Regulation.
The ERK/MAPK pathway is an important developmental signaling pathway. Mutations in upstream elements of this pathway result in neuro-cardio-facial cutaneous (NCFC) syndromes, which are typified by impaired neurocognitive abilities that are reliant upon hippocampal function. The role of ERK signaling during hippocampal development has not been examined and may provide critical insight into the cause of hippocampal dysfunction in NCFC syndromes. In this study, we have generated ERK1 and conditional ERK2 compound knock-out mice to determine the role of ERK signaling during development of the hippocampal dentate gyrus. We found that loss of both ERK1 and ERK2 resulted in 60% fewer granule cells and near complete absence of neural progenitor pools in the postnatal dentate gyrus. Loss of ERK1/2 impaired maintenance of neural progenitors as they migrate from the dentate ventricular zone to the dentate gyrus proper, resulting in premature depletion of neural progenitor cells beginning at E16.5, which prevented generation of granule cells later in development. Finally, loss of ERK2 alone does not impair development of the dentate gyrus as animals expressing only ERK1 developed a normal hippocampus. These findings establish that ERK signaling regulates maintenance of progenitor cells required for development of the dentate gyrus.
Departments of Neurosciences.
Joseph
http://orcid.org/0000-0002-1070-5237
J
Vithayathil
Departments of Neurosciences.
Joanna
http://orcid.org/0000-0002-4227-657X
J
Pucilowska
Pathology, and.
L Henry
LH
Goodnough
Biology, Case Western Reserve University, Cleveland, Ohio 44106.
Radhika P
RP
Atit
Departments of Neurosciences, gel2@case.edu.
Gary E
GE
Landreth
D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D018891:Dentate Gyrus / Q000196:embryology / Q000201:enzymology / Q000254:growth & development; D004622:Embryo, Mammalian; D025461:Feedback, Physiological / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D020547:Lateral Ventricles / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019950:Mitogen-Activated Protein Kinase 1; D009419:Nerve Tissue Proteins; D019908:Proto-Oncogene Proteins c-raf; C501070:RBBP8 protein, mouse; C535148:Mapk1 protein, mouse
ERK; MAPK pathway; NCFC; dentate gyrus; neurogenesis