Patterning of the antero‐ventral mammalian brain: Lessons from holoprosencephaly comparative biology in man and mouse

Barratt, Kristen S., Drover, Kyle A., Thomas, Zoë M., and Arkell, Ruth M. (2022) Patterning of the antero‐ventral mammalian brain: Lessons from holoprosencephaly comparative biology in man and mouse. WIREs Mechanisms of Disease, 14 (4). e1552.

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Adult form and function are dependent upon the activity of specialized signaling centers that act early in development at the embryonic midline. These centers instruct the surrounding cells to adopt a positional fate and to form the patterned structures of the phylotypic embryo. Abnormalities in these processes have devastating consequences for the individual, as exemplified by holoprosencephaly in which anterior midline development fails, leading to structural defects of the brain and/or face. In the 25 years since the first association between human holoprosencephaly and the sonic hedgehog gene, a combination of human and animal genetic studies have enhanced our understanding of the genetic and embryonic causation of this congenital defect. Comparative biology has extended the holoprosencephaly network via the inclusion of gene mutations from multiple signaling pathways known to be required for anterior midline formation. It has also clarified aspects of holoprosencephaly causation, showing that it arises when a deleterious variant is present within a permissive genome, and that environmental factors, as well as embryonic stochasticity, influence the phenotypic outcome of the variant. More than two decades of research can now be distilled into a framework of embryonic and genetic causation. This framework means we are poised to move beyond our current understanding of variants in signaling pathway molecules. The challenges now at the forefront of holoprosencephaly research include deciphering how the mutation of genes involved in basic cell processes can also cause holoprosencephaly, determining the important constituents of the holoprosencephaly permissive genome, and identifying environmental compounds that promote holoprosencephaly.

Item ID: 81350
Item Type: Article (Research - C1)
ISSN: 2692-9368
Copyright Information: © 2022 Wiley Periodicals LLC.
Funders: National Health and Medical Research Council (NHMRC)
Projects and Grants: NHMRC Grant/Award Number: 1126288
Date Deposited: 20 Mar 2024 03:14
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3208 Medical physiology > 320801 Cell physiology @ 100%
SEO Codes: 28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280103 Expanding knowledge in the biomedical and clinical sciences @ 100%
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