NEUROLOGICAL DISORDERS

Developmental disruptions

Huntington disease (HD) is a neurodegenerative disorder caused by an abnormally extended polyglutamine repeat in the protein huntingtin (HTT). However, whether and how mHTT affects early development of the brain in humans is not known. By examining tissue from fetuses carrying HD mutations, Barnat et al. reveal differences in early human brain development associated with mHTT and confirm these differences in HD model mice.

The authors procured cortical tissue from four HD-mutation carrier fetuses and four control fetuses at gestational week 13. At this stage, progenitor cells in the ventricular zone of the developing cortex undergo division, and their cell cycle correlates with the movement of their nuclei between the apical and basal surfaces of the neuroepithelial wall, in a process called interkinetic nuclear migration. Some of the cells arising from these divisions are cortical neurons that, in HD, degenerate later in life.

Credit: DiyanaDimitrova

Labelling for HTT and mHTT revealed that, in control tissue, HTT was localized at the apical-most processes (apical endfeet) of the progenitors but also spread diffusely to the basal surface. By contrast, in HD tissue, HTT was more concentrated in the apical endfeet. Similar differences in HTT localization were observed when comparing control mouse embryos (embryonic day 13.5) with embryos of two mouse models of HD, including one in which the first Htt exon was replaced with the human HTT exon carrying 111 CAG repeats (HdhQ111/Q111 mice).

Vesicle trafficking to the apical endfeet is important for maintaining progenitor cell polarity, and HTT is important for vesicle trafficking. Thus, the authors labelled various markers of the endosomal pathway as well as HTT in the fetal tissue to see if this pathway was affected in the developing HD brain. Indeed, the HD fetal tissue exhibited increases and decreases in the amount of colocalization of HTT with different markers, indicating that mHTT disrupts endosomal trafficking in the developing brain.

HTT regulates the trafficking of several proteins that form tight junctions between the apical endfeet of neighbouring progenitor cells that are needed to maintain the integrity of the neuroepithelium. Barnat et al. found that, in the control human and mouse developing cortex, HTT was partially colocalized with these tight junction proteins, which were enriched at the apical endfeet. However, in the HD tissue, some of these proteins were more abundant yet more restricted to the apical endfeet than in controls. Moreover, another such protein was downregulated in HD tissue. Co-immunoprecipitation of cortical extracts from HdhQ111/Q111 embryos revealed that binding of HTT to these tight junction proteins was reduced compared with controls. Thus, mHTT disrupts tight junction formation and thus the integrity of the neuroepithelium in early development.

Neuroepithelial integrity is necessary for interkinetic nuclear migration. Here, the authors examined the cell cycle of apical progenitors in cortical slices from HD and control mouse embryos. In slices from HdhQ111/Q111 mouse embryos, progenitor nuclei migrated between apical and basal sides more slowly than in control embryos, meaning that the G1 and G2 phases (with which these movements correlate) were extended. Moreover, the mitotic index in the developing cortex of HdhQ111/Q111 mice and HD mutation carrier fetuses was approximately half that of controls, suggesting reduced proliferation.

The progenitor cell cycle correlates with the assembly and disassembly of the primary cilia of these cells. Compared with controls, the cilia of progenitors in HdhQ111/Q111 mouse embryos and HD fetal cortex were more likely to be basolateral — reflecting the generation of basal progenitors committed to neurogenesis. In line with this, the HD samples also exhibited more basal progenitors in proliferative regions than did controls. Therefore, mHTT expression influences the proportions of different proliferative cell populations in the developing cortex.

“HD samples also exhibited more basal progenitors in proliferative regions than did controls”

Overall, this study provides evidence that HD-causing mutations in HTT disrupt early cortical development, suggesting that HD has a neurodevelopmental component.

References

Original article

  1. Barnat, M. et al. Huntington’s disease alters human neurodevelopment. Science 369, 787–793 (2020)

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Correspondence to Natasha Bray.

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Bray, N. Developmental disruptions. Nat Rev Neurosci 21, 592–593 (2020). https://doi.org/10.1038/s41583-020-0377-0

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