TY - JOUR
T1 - Postnatal age-differential ASD-like transcriptomic, synaptic, and behavioral deficits in Myt1l-mutant mice
AU - Kim, Seongbin
AU - Oh, Hyoseon
AU - Choi, Sang Han
AU - Yoo, Ye Eun
AU - Noh, Young Woo
AU - Cho, Yisul
AU - Im, Geun Ho
AU - Lee, Chanhee
AU - Oh, Yusang
AU - Yang, Esther
AU - Kim, Gyuri
AU - Chung, Won Suk
AU - Kim, Hyun
AU - Kang, Hyojin
AU - Bae, Yongchul
AU - Kim, Seong Gi
AU - Kim, Eunjoon
N1 - Publisher Copyright:
© 2022 The Author(s)
PY - 2022/9/20
Y1 - 2022/9/20
N2 - Myelin transcription factor 1 like (Myt1l), a zinc-finger transcription factor, promotes neuronal differentiation and is implicated in autism spectrum disorder (ASD) and intellectual disability. However, it remains unclear whether Myt1l promotes neuronal differentiation in vivo and its deficiency in mice leads to disease-related phenotypes. Here, we report that Myt1l-heterozygous mutant (Myt1l-HT) mice display postnatal age-differential ASD-related phenotypes: newborn Myt1l-HT mice, with strong Myt1l expression, show ASD-like transcriptomic changes involving decreased synaptic gene expression and prefrontal excitatory synaptic transmission and altered righting reflex. Juvenile Myt1l-HT mice, with markedly decreased Myt1l expression, display reverse ASD-like transcriptomes, increased prefrontal excitatory transmission, and largely normal behaviors. Adult Myt1l-HT mice show ASD-like transcriptomes involving astrocytic and microglial gene upregulation, increased prefrontal inhibitory transmission, and behavioral deficits. Therefore, Myt1l haploinsufficiency leads to ASD-related phenotypes in newborn mice, which are temporarily normalized in juveniles but re-appear in adults, pointing to continuing phenotypic changes long after a marked decrease of Myt1l expression in juveniles.
AB - Myelin transcription factor 1 like (Myt1l), a zinc-finger transcription factor, promotes neuronal differentiation and is implicated in autism spectrum disorder (ASD) and intellectual disability. However, it remains unclear whether Myt1l promotes neuronal differentiation in vivo and its deficiency in mice leads to disease-related phenotypes. Here, we report that Myt1l-heterozygous mutant (Myt1l-HT) mice display postnatal age-differential ASD-related phenotypes: newborn Myt1l-HT mice, with strong Myt1l expression, show ASD-like transcriptomic changes involving decreased synaptic gene expression and prefrontal excitatory synaptic transmission and altered righting reflex. Juvenile Myt1l-HT mice, with markedly decreased Myt1l expression, display reverse ASD-like transcriptomes, increased prefrontal excitatory transmission, and largely normal behaviors. Adult Myt1l-HT mice show ASD-like transcriptomes involving astrocytic and microglial gene upregulation, increased prefrontal inhibitory transmission, and behavioral deficits. Therefore, Myt1l haploinsufficiency leads to ASD-related phenotypes in newborn mice, which are temporarily normalized in juveniles but re-appear in adults, pointing to continuing phenotypic changes long after a marked decrease of Myt1l expression in juveniles.
KW - autism spectrum disorder
KW - CP: Neuroscience
KW - intellectual disability
KW - neurodevelopmental disorder
KW - neuronal differentiation
KW - schizophrenia
KW - social and repetitive behaviors
KW - synaptic transmission
KW - transcription factor
KW - transcriptome
UR - http://www.scopus.com/inward/record.url?scp=85138142021&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2022.111398
DO - 10.1016/j.celrep.2022.111398
M3 - Article
C2 - 36130507
AN - SCOPUS:85138142021
SN - 2211-1247
VL - 40
JO - Cell Reports
JF - Cell Reports
IS - 12
M1 - 111398
ER -