Zac1Regulates the Differentiation and Migration of Neocortical Neurons viaPac1
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 
Published: September 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 geneZac1.In humans, either loss or gain ofZAC1expression is associated with reduced growth rates and intellectual disability. To test whether increasedZac1expression directly perturbs neurodevelopment, we misexpressedZac1in murine neocortical progenitors. The effects were striking:Zac1delayed the transition of apical radial glial cells to basal intermediate neuronal progenitors and postponed their subsequent differentiation into neurons.Zac1misexpression also blocked neuronal migration, withZac1-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 onZac1knockdown, indicating thatZac1levels must be regulated precisely. Finally,Zac1controlled neuronal migration by regulatingPac1transcription, a receptor for the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP).Pac1andZac1loss- and gain-of-function presented as phenocopies, and overexpression ofPac1rescued theZac1knockdown neuronal migration phenotype. Thus, dysregulatedZac1expression 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 STATEMENTAltered 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, only a handful of imprinted genes are known or suspected to regulate brain development (e.g.,Dlk1,Peg3,Ube3a,necdin, andGrb10). Herein we show that the maternally imprinted geneZac1is a critical regulator of neocortical development. Our studies are relevant because loss of 6q24 maternal imprinting in humans results in elevatedZAC1expression, which has been associated with neurocognitive defects.