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2 deletion, and more generally, in the pathophysiology of ADHD and ASD. The chromosome 16p11.2 CNV encompasses 26 genes (the 16p11 genes) that are highly conserved on mouse chromosome 7F3 ( Figure?1A). To generate a mouse model of the 16p11.2 deletion, we introduced LoxP sites flanking the genes deleted in human patients ( Figures 1B, S1A, and S1B). The targeting strategy also included an mCherry reporter gene coupled to deletion of the region. Successful targeting of mouse embryonic stem cells (mESCs) was verified by Southern blotting and PCR ( Figures S1C�CS1I; Table S1). The modified mESCs were injected into blastocysts, implanted into pseudopregnant female mice, and chimeric offspring were subsequently bred to (1) C57BL/6N females to produce heterozygous floxed (16p11flx/+) mice [http://www.selleckchem.com/products/AG-014699.html Rucaparib research buy] and (2) HPRT-Cre transgenic females ( Tang et?al., 2002) to produce mice lacking one copy of the 16p11 genes (16p11+/?). Heterozygous deletion was confirmed by PCR genotyping, as well as mCherry fluorescence ( Figures 1B, inset, and 1C). Quantitative real-time RT-PCR (qPCR) analysis of neonate brain RNA showed a global reduction in transcription of 40%�C60% for the 16p11 genes upon loss of one copy ( Figure?1D). F1 and further generations of 16p11+/? male mice were consequently backbred to C57BL/6N females. 16p11+/? mice [http://www.selleckchem.com/ALK.html find protocol] were born at Mendelian ratios. As adults, they showed a 12.2% reduction in average body length (p?= 5.09?�� 10?7; Figures 1E and 1F), a reduction in the accumulation of abdominal fat pads, and significantly reduced body weight starting at early postnatal age ( Figure?1G). A small number of 16p11+/? animals recovered to nearly normal body weight in adulthood. Severely affected mice were runty and died within the first postnatal weeks ( Figure?1H), resulting in lower-than-Mendelian ratios of survivors past the age of tagging (typically 6?weeks). An improved nutritional regimen and alleviated competition by wild-type siblings rescued 16p11+/? pup viability to 60% of Mendelian expectation ( Figure?1H; Supplemental Experimental Procedures). Food intake in adult 16p11+/? animals was normal ( Figure?1I). 16p11+/? pups appeared hyperactive and displayed severe [http://en.wikipedia.org/wiki/Fluconazole Fluconazole] deficits in motor coordination including tumbling and tremor ( Movie S1). These findings were replicated and quantified in adult animals as described below. In contrast to?the decreased body size, the brain weight of 16p11+/? mice was indistinguishable from controls ( Figure?1J) throughout development, with the exception of 1-week-old (P7) pups, in which the brain weight was mildly reduced (p?