TMEM161B modulates radial glial scaffolding in neocortical development

Abstract

TMEM161B encodes an evolutionarily conserved widely expressed novel 8-pass transmembrane protein of unknown function in human. Here we identify TMEM161B homozygous hypomorphic missense variants in our recessive polymicrogyria (PMG) cohort. Patients carrying TMEM161B mutations exhibit striking neocortical PMG and intellectual disability. Tmem161b knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and patient-derived brain organoids show defects in apical cell polarity and radial glial scaffolding. We found that TMEM161B modulates actin filopodia, functioning upstream of the Rho-GTPase CDC42. Our data link TMEM161B with human PMG, likely regulating radial glia apical polarity during neocortical development.

Shaping the brain: The emergence of cortical structure and folding

“…Disrupting Tmem161b function in cortical progenitors in ferrets led to decreased gyral size and sulci depth, confirming its role in promoting normal cortical gyration 119 . Furthermore, Tmem161b plays also a role in the integrity of the RG fiber scaffold, which as described above is different locally between proto-gyri and proto-sulci 120 . Overall, these findings, especially in context of the ferret studies examining Shh stimulation of HOPX+ bRGCs described above, suggest a decreased sensitivity to Shh signaling in a developing gyrencephalic cortex deficient in Tmem161b, which provides important insights into the pathogenic mechanisms underlying the polymicrogyria syndrome described in patients.…”

“…In addition, mutations in genes involved in modulating Shh signaling have also been linked to non-holoprosencephaly cortical malformations, providing further support to the notion that disrupted Shh signaling can lead to defects in cortical folding. These include the microcephaly/cerebellar hypoplasia associated with recessive mutations in CHMP1A 112 , 118 , and the recently described polymicrogyria syndrome caused by bi-allelic mutations in TMEM161B 119 , 120 . While disruption of TMEM161B through bi-allelic missense mutations in humans causes cortical gyration abnormalities, loss of Tmem161b function in mice causes several Shh-related malformations such as holoprosencephaly, eye defects, and craniofacial abnormalities, as well as morphologically abnormal primary cilia in the ventricular zone of the developing cortex 119 .…”

Fins, fur, and wings: the study of Tmem161b across species, and what it tells us about its function in the heart

“…In two recent back-to-back studies, the range of phenotypes in Tmem161b knockout mice was extended further (Akula et al 2023 ; Wang et al 2023 ). Tmem161b knockout mice showed holoprosencephaly (a failure of the forebrain hemispheres to separate) as well as a range of other midline fusion defects.…”

“…Tmem161b knockout mice showed holoprosencephaly (a failure of the forebrain hemispheres to separate) as well as a range of other midline fusion defects. These defects appeared fully penetrant but with variable expressivity, and included cleft lip/palate, asymmetric eye defects and even instances of cyclopia (Akula et al 2023 ; Wang et al 2023 ). Growth defects and perinatal lethality were also reported, corroborating an earlier report (Akula et al 2023 ; Koopman et al 2021 ; Wang et al 2023 ).…”

“…These defects appeared fully penetrant but with variable expressivity, and included cleft lip/palate, asymmetric eye defects and even instances of cyclopia (Akula et al 2023 ; Wang et al 2023 ). Growth defects and perinatal lethality were also reported, corroborating an earlier report (Akula et al 2023 ; Koopman et al 2021 ; Wang et al 2023 ). In developing brains, the cortical layer was thinner in knockout embryos and neurons were mispatterned, which were attributed to defects in either neural cell migration or cell fate acquisition (Akula et al 2023 ; Wang et al 2023 ).…”