ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities.
Germline mutations in the RAS/ERK signaling pathway underlie several related developmental disorders collectively termed neuro-cardio-facial-cutaneous (NCFC) syndromes. NCFC patients manifest varying degrees of cognitive impairment, but the developmental basis of their brain abnormalities remains largely unknown. Neurofibromatosis type 1 (NF1), an NCFC syndrome, is caused by loss-of-function heterozygous mutations in the NF1 gene, which encodes neurofibromin, a RAS GTPase-activating protein. Here, we show that biallelic Nf1 inactivation promotes Erk-dependent, ectopic Olig2 expression specifically in transit-amplifying progenitors, leading to increased gliogenesis at the expense of neurogenesis in neonatal and adult subventricular zone (SVZ). Nf1-deficient brains exhibit enlarged corpus callosum, a structural defect linked to severe learning deficits in NF1 patients. Strikingly, these NF1-associated developmental defects are rescued by transient treatment with an MEK/ERK inhibitor during neonatal stages. This study reveals a critical role for Nf1 in maintaining postnatal SVZ-derived neurogenesis and identifies a potential therapeutic window for treating NF1-associated brain abnormalities.
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Yuan
Y
Wang
Edward
E
Kim
Xiaojing
X
Wang
Bennett G
BG
Novitch
Kazuaki
K
Yoshikawa
Long-Sheng
LS
Chang
Yuan
Y
Zhu
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001921:Brain / Q000473:pathology*; D003337:Corpus Callosum / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000473:pathology*; D009456:Neurofibromatosis 1 / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000473:pathology; D000076104:Oligodendrocyte Transcription Factor 2
D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D025542:Neurofibromin 1; D000076104:Oligodendrocyte Transcription Factor 2; C512773:Olig2 protein, mouse