Cilia, ciliopathies and hedgehog-related forebrain developmental disorders

• Published in: Neurobiology of disease 2021-03, Vol.150, p.105236-105236, Article 105236
• Main Authors: Andreu-Cervera, Abraham, Catala, Martin, Schneider-Maunoury, Sylvie
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - embryology; Abnormalities, Multiple - genetics; Brain - abnormalities; Brain - embryology; Brain development; Cerebellum - abnormalities; Cerebellum - embryology; Cerebral cortex; Cilia - genetics; Ciliary Motility Disorders - embryology; Ciliary Motility Disorders - genetics; Ciliopathies - embryology; Ciliopathies - genetics; Ciliopathy; Craniofacial Abnormalities - embryology; Craniofacial Abnormalities - genetics; Developmental Disabilities - genetics; Encephalocele - embryology; Encephalocele - genetics; Eye Abnormalities - embryology; Eye Abnormalities - genetics; Forebrain; Gene Expression Regulation, Developmental; Gli transcription factor; Hedgehog Proteins - physiology; Holoprosencephaly; Holoprosencephaly - embryology; Holoprosencephaly - genetics; Humans; Kidney Diseases, Cystic - embryology; Kidney Diseases, Cystic - genetics; Life Sciences; Microcephaly; Neurons and Cognition; Polycystic Kidney Diseases - embryology; Polycystic Kidney Diseases - genetics; Primary cilia; Prosencephalon - embryology; Retina - abnormalities; Retina - embryology; Retinitis Pigmentosa - embryology; Retinitis Pigmentosa - genetics; RPGRIP1L; Signal Transduction; Sonic hedgehog; Zinc Finger Protein GLI1 - genetics; Zinc Finger Protein Gli2 - genetics; Zinc Finger Protein Gli3 - genetics
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2020.105236

Development of the forebrain critically depends on the Sonic Hedgehog (Shh) signaling pathway, as illustrated in humans by the frequent perturbation of this pathway in holoprosencephaly, a condition defined as a defect in the formation of midline structures of the forebrain and face. The Shh pathway requires functional primary cilia, microtubule-based organelles present on virtually every cell and acting as cellular antennae to receive and transduce diverse chemical, mechanical or light signals. The dysfunction of cilia in humans leads to inherited diseases called ciliopathies, which often affect many organs and show diverse manifestations including forebrain malformations for the most severe forms. The purpose of this review is to provide the reader with a framework to understand the developmental origin of the forebrain defects observed in severe ciliopathies with respect to perturbations of the Shh pathway. We propose that many of these defects can be interpreted as an imbalance in the ratio of activator to repressor forms of the Gli transcription factors, which are effectors of the Shh pathway. We also discuss the complexity of ciliopathies and their relationships with forebrain disorders such as holoprosencephaly or malformations of cortical development, and emphasize the need for a closer examination of forebrain defects in ciliopathies, not only through the lens of animal models but also taking advantage of the increasing potential of the research on human tissues and organoids. •Primary cilia are sensory and signaling organelles with central role in brain development.•Severe human ciliopathies encompass forebrain developmental malformations.•Forebrain malformations in ciliopathies overlap with microcephaly and holoprosencephaly.•Several forebrain developmental defects in ciliopathies can be attributed to Hedgehog/Gli perturbations.