TMEM161B regulates cerebral cortical gyration, Sonic Hedgehog signaling, and ciliary structure in the developing central nervous system

Abstract

Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B , which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the Tmem161b null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify TMEM161B as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.

Investigation of the mechanisms underlying the development and evolution of folds of the cerebrum using gyrencephalic ferrets

“…Conversely, suppressing Shh signaling with HhipΔC22 inhibited the formation of folds. Consistently, inhibition of TMEM161B, which regulates Shh signaling, suppressed cortical folding in the ferret cerebrum (Akula et al, 2023). These findings strongly indicate that FGF signaling and Shh signaling work in concert to regulate the formation of cortical folds (Figure 4a) (Masuda et al, 2015;Matsumoto et al, 2017Matsumoto et al, , 2020.…”

TMEM161B modulates radial glial scaffolding in neocortical development

“…The apical junction is also the site of ciliary protrusion in polarized epithelia, and in the accompanying paper, Akula et al. ( 34 ) observed disruption of apical primary cilia in Tmem161b KO mice, in line with a role in RGC polarity ( 35 ).…”

Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria

“…Sequencing of our cohort identified polymicrogyria cases associated with de novo variants in SCN2A, as well as rare inherited variants in TMEM161B, KIF26A , and MAN2C1 . Details of these associations have been recently reported ( TMEM161B , MAN2C1 , KIF26A , and SCN2A ).…”