Zac1 Regulates the Differentiation and Migration of Neocortical Neurons via Pac1

• Published in: The Journal of neuroscience 2015-09, Vol.35 (39), p.13430-13447
• Main Authors: Adnani, Lata, Langevin, Lisa Marie, Gautier, Elodie, Dixit, Rajiv, Parsons, Kari, Li, Saiqun, Kaushik, Gaurav, Wilkinson, Grey, Wilson, Richard, Childs, Sarah, Nguyen, Minh Dang, Journot, Laurent, Dehay, Colette, Schuurmans, Carol
• Format: Article
• Language: English
• Subjects: Animals; Cell Cycle Proteins - genetics; Cell Cycle Proteins - physiology; Cell Differentiation - physiology; Cell Movement - genetics; Cell Movement - physiology; Cell Proliferation; Development Biology; Embryology and Organogenesis; Female; Gene Knockdown Techniques; Genes, Tumor Suppressor - physiology; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Neocortex - cytology; Neocortex - embryology; Neurites - physiology; Neurites - ultrastructure; Neurons - physiology; Neurons - ultrastructure; Pregnancy; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I - genetics; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I - physiology; Transcription Factors - genetics; Transcription Factors - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0777-15.2015

Imprinted genes are dosage sensitive, and their dysregulated expression is linked to disorders of growth and proliferation, including fetal and postnatal growth restriction. Common sequelae of growth disorders include neurodevelopmental defects, some of which are indirectly related to placental insufficiency. However, several growth-associated imprinted genes are also expressed in the embryonic CNS, in which their aberrant expression may more directly affect neurodevelopment. To test whether growth-associated genes influence neural lineage progression, we focused on the maternally imprinted gene Zac1. In humans, either loss or gain of ZAC1 expression is associated with reduced growth rates and intellectual disability. To test whether increased Zac1 expression directly perturbs neurodevelopment, we misexpressed Zac1 in murine neocortical progenitors. The effects were striking: Zac1 delayed the transition of apical radial glial cells to basal intermediate neuronal progenitors and postponed their subsequent differentiation into neurons. Zac1 misexpression also blocked neuronal migration, with Zac1-overexpressing neurons pausing more frequently and forming fewer neurite branches during the period when locomoting neurons undergo dynamic morphological transitions. Similar, albeit less striking, neuronal migration and morphological defects were observed on Zac1 knockdown, indicating that Zac1 levels must be regulated precisely. Finally, Zac1 controlled neuronal migration by regulating Pac1 transcription, a receptor for the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP). Pac1 and Zac1 loss- and gain-of-function presented as phenocopies, and overexpression of Pac1 rescued the Zac1 knockdown neuronal migration phenotype. Thus, dysregulated Zac1 expression has striking consequences on neocortical development, suggesting that misexpression of this transcription factor in the brain in certain growth disorders may contribute to neurocognitive deficits. Significance statement: Altered expression of imprinted genes is linked to cognitive dysfunction and neuropsychological disorders, such as Angelman and Prader-Willi syndromes, and autism spectrum disorder. Mouse models have also revealed the importance of imprinting for brain development, with chimeras generated with parthenogenetic (two maternal chromosomes) or androgenetic (two paternal chromosomes) cells displaying altered brain sizes and cellular defects. Despite these striking phenotypes, onl