Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development.
The regulated proliferation and differentiation of neural stem cells before the generation and migration of neurons in the cerebral cortex are central aspects of mammalian development. Periventricular neuronal heterotopia, a specific form of mislocalization of cortical neurons, can arise from neuronal progenitors that fail to negotiate aspects of these developmental processes. Here we show that mutations in genes encoding the receptor-ligand cadherin pair DCHS1 and FAT4 lead to a recessive syndrome in humans that includes periventricular neuronal heterotopia. Reducing the expression of Dchs1 or Fat4 within mouse embryonic neuroepithelium increased progenitor cell numbers and reduced their differentiation into neurons, resulting in the heterotopic accumulation of cells below the neuronal layers in the neocortex, reminiscent of the human phenotype. These effects were countered by concurrent knockdown of Yap, a transcriptional effector of the Hippo signaling pathway. These findings implicate Dchs1 and Fat4 upstream of Yap as key regulators of mammalian neurogenesis.
Helmholtz Center Munich, German Research Center for Environmental Health, Institute for Stem Cell Research, Neuherberg, Germany.
Silvia
S
Cappello
Mary J
MJ
Gray
Caroline
C
Badouel
Simona
S
Lange
Melanie
M
Einsiedler
Myriam
M
Srour
David
D
Chitayat
Fadi F
FF
Hamdan
Zandra A
ZA
Jenkins
Tim
T
Morgan
Nadia
N
Preitner
Tami
T
Uster
Jackie
J
Thomas
Patrick
P
Shannon
Victoria
V
Morrison
Nataliya
N
Di Donato
Lionel
L
Van Maldergem
Teresa
T
Neuhann
Ruth
R
Newbury-Ecob
Marielle
M
Swinkells
Paulien
P
Terhal
Louise C
LC
Wilson
Petra J G
PJ
Zwijnenburg
Andrew J
AJ
Sutherland-Smith
Michael A
MA
Black
David
D
Markie
Jacques L
JL
Michaud
Michael A
MA
Simpson
Sahar
S
Mansour
Helen
H
McNeill
Magdalena
M
Götz
Stephen P
SP
Robertson
D000015:Abnormalities, Multiple / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000235:genetics; D005532:Foot Deformities, Congenital / Q000235:genetics; D055785:Gene Knockdown Techniques; D006228:Hand Deformities, Congenital / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D007593:Joint Instability / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D054091:Periventricular Nodular Heterotopia / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D000070585:Cadherin Related Proteins; D015820:Cadherins; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C442479:DCHS1 protein, human; C534294:FAT4 protein, human; C486223:Yap1 protein, mouse