Disrupted ERK signaling during cortical development leads to abnormal progenitor proliferation, neuronal and network excitability and behavior, modeling human neuro-cardio-facial-cutaneous and related syndromes.
Genetic disorders arising from copy number variations in the ERK (extracellular signal-regulated kinase) MAP (mitogen-activated protein) kinases or mutations in their upstream regulators that result in neuro-cardio-facial-cutaneous syndromes are associated with developmental abnormalities, cognitive deficits, and autism. We developed murine models of these disorders by deleting the ERKs at the beginning of neurogenesis and report disrupted cortical progenitor generation and proliferation, which leads to altered cytoarchitecture of the postnatal brain in a gene-dose-dependent manner. We show that these changes are due to ERK-dependent dysregulation of cyclin D1 and p27(Kip1), resulting in cell cycle elongation, favoring neurogenic over self-renewing divisions. The precocious neurogenesis causes premature progenitor pool depletion, altering the number and distribution of pyramidal neurons. Importantly, loss of ERK2 alters the intrinsic excitability of cortical neurons and contributes to perturbations in global network activity. These changes are associated with elevated anxiety and impaired working and hippocampal-dependent memory in these mice. This study provides a novel mechanistic insight into the basis of cortical malformation which may provide a potential link to cognitive deficits in individuals with altered ERK activity.
Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106-4928, USA.
Joanna
J
Pucilowska
Pavel A
PA
Puzerey
J Colleen
JC
Karlo
Roberto F
RF
Galán
Gary E
GE
Landreth
D000818:Animals; D000963:Antimetabolites; D001007:Anxiety / Q000235:genetics / Q000523:psychology; D001522:Behavior, Animal / Q000502:physiology*; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000254:growth & development / Q000473:pathology / Q000502:physiology*; D003072:Cognition Disorders / Q000235:genetics / Q000523:psychology; D003216:Conditioning, Operant / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009415:Nerve Net / Q000502:physiology*; D009422:Nervous System Diseases / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*
D000963:Antimetabolites; D048049:Extracellular Signal-Regulated MAP Kinases; D001973:Bromodeoxyuridine