RT Journal Article
SR Electronic
T1 A MYT1L Syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.17.423095
DO 10.1101/2020.12.17.423095
A1 Jiayang Chen
A1 Mary E. Lambo
A1 Xia Ge
A1 Joshua T. Dearborn
A1 Yating Liu
A1 Katherine B. McCullough
A1 Raylynn G. Swift
A1 Dora R. Tabachnick
A1 Lucy Tian
A1 Kevin Noguchi
A1 Joel R. Garbow
A1 Harrison W. Gabel
A1 Keith B. Hengen
A1 Susan E. Maloney
A1 Joseph D. Dougherty
YR 2020
UL http://biorxiv.org/content/early/2020/12/17/2020.12.17.423095.abstract
AB Human genetics have defined a new autism-associated syndrome caused by loss-of-function mutations in MYT1L, a transcription factor known for enabling fibroblast-to-neuron conversions. However, how MYT1L mutation causes autism, ADHD, intellectual disability, obesity, and brain anomalies is unknown. Here, we develop a mouse model of this syndrome. Physically, Myt1l haploinsufficiency causes obesity, white-matter thinning, and microcephaly in the mice, mimicking clinical phenotypes. Studies during brain development reveal disrupted gene expression, mediated in part by loss of Myt1l gene target activation, and highlight precocious neuronal differentiation as the mechanism for microcephaly. In contrast, adult studies reveal that mutation results in failure of transcriptional and chromatin maturation, echoed in disruptions in baseline physiological properties of neurons. This results in behavioral features including hyperactivity, hypotonia, and social alterations, with more severe phenotypes in males. Overall, these studies provide insight into the mechanistic underpinnings of this disorder and enable future preclinical studies.Competing Interest StatementThe authors have declared no competing interest.