Heterozygosity for Nuclear Factor One X in mice reveals neurological features of Malan syndrome

摘要

Haploinsufficiency of the Nuclear Factor One X (NFIX) gene in human results in Malan syndrome, which is characterised by macrocephaly and intellectual disability. However, it remains unclear how NFIX deficiency leads to this macrocephalic pheno- type and how this affects cortical connectivity and behavioural function. Previous work has identified NFIX, which is a transcrip- tion factor, as a crucial regulator for the timely differentiation of intermediate progenitor cells within the developing mouse brain. In the present study, we used the Nfix-heterozygous mouse model to investigate the underlying functional conse- quences of the macrocephaly and intellectual disability features of NFIX-haploinsufficient Malan syndrome patients. Using diffusion- weighted magnetic resonance imaging and tractography analyses, we reveal that adult Nfix-heterozygous mouse have increased brain volume, loss of axonal integrity within major commissures, and abnormal structural connectivity. Using immunohistochem- istry and confocal microscopy, we found that Nfix-heterozygous mice display enlarged cerebral cortices due to an expansion of the upper cortical layers. Behaviourally, Nfix-heterozygous mice exhibit learning and memory deficits, as well as abnormal social behaviour reminiscent of autistic-like traits. Taken together, these data are the first to provide insights into the underlying basis of the neurological symptoms associated with Malan syndrome patients.