Neurodevelopmental mechanisms in 17q12 CNV disorders and autism

PROJECT SUMMARY Copy number variants (CNVs) are contiguous gene deletions or duplications that confer susceptibility to neuro- psychiatric and neurodevelopmental disorders (NDDs). Thereby, CNVs offer a powerful opportunity to investi- gate multigenic mechanisms in complex brain disease. Recent studies demonstrate that the 17q12 Deletion

(17qDel) is among the strongest CNV risk factors for autism; however, the mechanisms of circuit dysgenesis caused by 17q12Dels remain poorly understood. The objective of this research is to define defective neurode- velopmental mechanisms caused by 17q12 CNVs, particularly 17q12Dels, which represent a high-penetrant,

high-confidence risk factor for autism and related neurodevelopmental disorders (NDDs). To meet this objec- tive, we have generated unique experimental resources, including: a 17q12Del mouse; and human 17q12 CNV induced pluripotent stem cells (iPSCs) (with robust controls), from patients with 17q12Dels, as well as from pa-

tients with reciprocal 17q12 duplications. Our central hypothesis is that the combinatorial haploinsufficiency of the genes within the interval, including the transcription factor Lhx1, a known regulator of Wnt signaling, dis- rupts multiple steps in brain and circuit development. Notably, we have discovered that 17q12Del mice exhibit

a spectrum of anterior brain and craniofacial abnormalities. These phenotypes vary depending on the mouse genetic background, and are akin to, but milder than, the Lhx1-null mouse. The 17q12Del on the inbred C57BL/6N background displays greater phenotypic severity, including neonatal lethality, compared to

17q12Del mice on the outbred CD-1 background, that survive into adulthood with milder cortical and hippo- campal abnormalities. We will pursue the following Aims: 1) Define defective transcriptional mechanisms and molecular pathways in embryonic brain development in 17q12Del mice; 2) Define defective molecular path-

ways and rescue strategies in patient-derived 17q12 CNV neurons; and 3) Define postnatal neurodevelopmen- tal and behavioral abnormalities in 17q12Del mice on diverse background genetics using MRI morphometry, molecular and behavioral studies. This research will have a sustained impact on the field given the high level

of significance and innovation: 1) 17q12Dels represent an understudied, high-confidence autism locus; 2) the study of Wnt signaling will permit convergence of the 17q12Del mutation with other high-confidence autism genes; 3) we are testing proof-of-concept Wnt-related therapeutics; 4) methodologically, study of an autism-

associated mutation on diverse, mouse genetic backgrounds provides an important, experimental paradigm for investigating phenotypic heterogeneity; and 5) we use an integrated translational approach, that involves a multidisciplinary team coordinating cross-species experiments, including in vivo rodent and in vitro human

iPSC models, with clinical studies in patients. This research will permit bench-to-bedside and broadly-signifi- cant discoveries related to the diversity of phenotypes and treatment responses in neuropsychiatric disorders.