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TMEM161B modulates radial glial scaffolding in neocortical development
Lu Wang1,2, Caleb Heffner3, Keng Ioi Vong1,2
1Department of Neurosciences, University of California San Diego, La Jolla, CA 92093.
Mutations in TMEM161B cause polymicrogyria (PMG) and intellectual disability by disrupting brain development. This study reveals TMEM161B
Area of Science:
- Genetics and Developmental Neuroscience
- Molecular and Cellular Biology
Background:
- TMEM161B is a novel transmembrane protein with an unknown function.
- Polymicrogyria (PMG) is a developmental brain malformation characterized by abnormal cortical folding.
Purpose of the Study:
- To investigate the function of TMEM161B in human brain development.
- To identify the genetic cause of recessive polymicrogyria in a patient cohort.
Main Methods:
- Genetic sequencing to identify TMEM161B variants in patients with PMG.
- Generation and analysis of Tmem161b knockout mice.
- Utilizing patient-derived brain organoids to study cellular mechanisms.
- Investigating TMEM161B's role in actin dynamics and Rho-GTPase signaling.
Main Results:
- Identified homozygous hypomorphic TMEM161B missense variants in patients with PMG and intellectual disability.
- Tmem161b knockout mice exhibit failed midline hemispheric cleavage.
- Patient mutations and derived organoids show defects in apical cell polarity and radial glial scaffolding.
- TMEM161B modulates actin filopodia upstream of CDC42.
Conclusions:
- TMEM161B is essential for proper neocortical development in humans and mice.
- TMEM161B mutations lead to polymicrogyria by disrupting radial glia apical polarity.
- This study links TMEM161B to human PMG and provides insights into its molecular function.
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