Abstract
Focal malformations of cortical development (FMCDs), including focal cortical dysplasia (FCD) and hemimegalencephaly (HME), are major etiologies of pediatric intractable epilepsies exhibiting cortical dyslamination. Brain somatic mutations in MTOR have recently been identified as a major genetic cause of FMCDs. However, the molecular mechanism by which these mutations lead to cortical dyslamination remains poorly understood. Here, using patient tissue, genome-edited cells, and mouse models with brain somatic mutations in MTOR, we discovered that disruption of neuronal ciliogenesis by the mutations underlies cortical dyslamination in FMCDs. We found that abnormal accumulation of OFD1 at centriolar satellites due to perturbed autophagy was responsible for the defective neuronal ciliogenesis. Additionally, we found that disrupted neuronal ciliogenesis accounted for cortical dyslamination in FMCDs by compromising Wnt signals essential for neuronal polarization. Altogether, this study describes a molecular mechanism by which brain somatic mutations in MTOR contribute to the pathogenesis of cortical dyslamination in FMCDs. Park et al. demonstrate that brain somatic mutations in MTOR result in defective neuronal ciliogenesis in FMCDs. The aberrant accumulation of OFD1 by impaired autophagy is responsible for defective ciliogenesis. Moreover, defective ciliogenesis accounts for cortical dyslamination in FMCDs by compromising Wnt signals.
| Original language | English |
|---|---|
| Pages (from-to) | 83-97.e7 |
| Journal | Neuron |
| Volume | 99 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2018 Jul 11 |
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All Science Journal Classification (ASJC) codes
- Neuroscience(all)
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Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination. / Park, Sang Min; Lim, Jae Seok; Ramakrishina, Suresh; Kim, Se Hoon; Kim, Woo Kyeong; Lee, Junehawk; Kang, Hoon Chul; Reiter, Jeremy F.; Kim, Dong Seok; Kim, Hyongbum (Henry); Lee, Jeong Ho.
In: Neuron, Vol. 99, No. 1, 11.07.2018, p. 83-97.e7.Research output: Contribution to journal › Article
TY - JOUR
T1 - Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination
AU - Park, Sang Min
AU - Lim, Jae Seok
AU - Ramakrishina, Suresh
AU - Kim, Se Hoon
AU - Kim, Woo Kyeong
AU - Lee, Junehawk
AU - Kang, Hoon Chul
AU - Reiter, Jeremy F.
AU - Kim, Dong Seok
AU - Kim, Hyongbum (Henry)
AU - Lee, Jeong Ho
PY - 2018/7/11
Y1 - 2018/7/11
N2 - Focal malformations of cortical development (FMCDs), including focal cortical dysplasia (FCD) and hemimegalencephaly (HME), are major etiologies of pediatric intractable epilepsies exhibiting cortical dyslamination. Brain somatic mutations in MTOR have recently been identified as a major genetic cause of FMCDs. However, the molecular mechanism by which these mutations lead to cortical dyslamination remains poorly understood. Here, using patient tissue, genome-edited cells, and mouse models with brain somatic mutations in MTOR, we discovered that disruption of neuronal ciliogenesis by the mutations underlies cortical dyslamination in FMCDs. We found that abnormal accumulation of OFD1 at centriolar satellites due to perturbed autophagy was responsible for the defective neuronal ciliogenesis. Additionally, we found that disrupted neuronal ciliogenesis accounted for cortical dyslamination in FMCDs by compromising Wnt signals essential for neuronal polarization. Altogether, this study describes a molecular mechanism by which brain somatic mutations in MTOR contribute to the pathogenesis of cortical dyslamination in FMCDs. Park et al. demonstrate that brain somatic mutations in MTOR result in defective neuronal ciliogenesis in FMCDs. The aberrant accumulation of OFD1 by impaired autophagy is responsible for defective ciliogenesis. Moreover, defective ciliogenesis accounts for cortical dyslamination in FMCDs by compromising Wnt signals.
AB - Focal malformations of cortical development (FMCDs), including focal cortical dysplasia (FCD) and hemimegalencephaly (HME), are major etiologies of pediatric intractable epilepsies exhibiting cortical dyslamination. Brain somatic mutations in MTOR have recently been identified as a major genetic cause of FMCDs. However, the molecular mechanism by which these mutations lead to cortical dyslamination remains poorly understood. Here, using patient tissue, genome-edited cells, and mouse models with brain somatic mutations in MTOR, we discovered that disruption of neuronal ciliogenesis by the mutations underlies cortical dyslamination in FMCDs. We found that abnormal accumulation of OFD1 at centriolar satellites due to perturbed autophagy was responsible for the defective neuronal ciliogenesis. Additionally, we found that disrupted neuronal ciliogenesis accounted for cortical dyslamination in FMCDs by compromising Wnt signals essential for neuronal polarization. Altogether, this study describes a molecular mechanism by which brain somatic mutations in MTOR contribute to the pathogenesis of cortical dyslamination in FMCDs. Park et al. demonstrate that brain somatic mutations in MTOR result in defective neuronal ciliogenesis in FMCDs. The aberrant accumulation of OFD1 by impaired autophagy is responsible for defective ciliogenesis. Moreover, defective ciliogenesis accounts for cortical dyslamination in FMCDs by compromising Wnt signals.
UR - http://www.scopus.com/inward/record.url?scp=85048266703&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048266703&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2018.05.039
DO - 10.1016/j.neuron.2018.05.039
M3 - Article
C2 - 29937275
AN - SCOPUS:85048266703
VL - 99
SP - 83-97.e7
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 1
ER -