SUMMARY An understanding of how heterozygous loss-of-function mutations in ASD risk genes, such as TBR1, contribute to ASD remains elusive. Conditional Tbr1 deletion during late mouse gestation in cortical layer 6 neurons (Tbr1layer6 mutants) provides novel insights into its function, including dendritic patterning, synaptogenesis, and cell intrinsic physiology. These phenotypes occur in heterozygotes, providing insights into mechanisms that may underlie ASD pathophysiology. Restoring expression of Wnt7b, largely rescues the synaptic deficit in Tbr1layer6 mutant neurons. Furthermore, Tbr1layer6 heterozygotes have increased anxiety-like behavior, a phenotype seen ASD. Integrating TBR1 ChIP-Seq and RNA-Seq data from layer 6 neurons, and activity of TBR1 bound candidate enhancers, provides evidence for how TBR1 regulates layer 6 properties. Moreover, several putative TBR1 targets are ASD risk genes, placing TBR1 in a central position both for ASD risk and for regulating transcriptional circuits that control multiple steps in layer 6 development essential for the assembly of neural circuits.

Highlights d Most mouse Cre driver lines tested exhibited variable rates of germline recombination d Germline recombination exhibits parental sex bias and target locus selectivity d Similar principles apply to multiple organisms and recombinase systems d Guidelines are provided for detecting and minimizing unwanted germline recombination

Highlights d Mafb and c-Maf are expressed in MGE-derived CINs but not projection neurons d Mafb and c-Maf control the numbers of MGE-lineage CINs d Loss of Mafb and c-Maf leads to increased SST + CIN perinatally d Mafb and c-Maf control CIN synaptic maturation antagonistically

Neurofibromatosis 1 (NF1) is caused by mutations in theNF1gene, which encodes the protein, neurofibromin, an inhibitor of Ras activity. Cortical GABAergic interneurons (CINs) are implicated in NF1 pathology, but the cellular and molecular changes to CINs are unknown. We deleted mouseNf1from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin.Nf1loss led to a persistence of immature oligodendrocytes that prevented later-generated oligodendrocytes from occupying the cortex. Moreover, molecular and cellular properties of parvalbumin (PV)-positive CINs were altered by the loss ofNf1, without changes in somatostatin (SST)-positive CINs. We discovered that loss ofNf1results in a dose-dependent decrease inLhx6expression, the transcription factor necessary to establish SST+and PV+CINs, which was rescued by the MEK inhibitor SL327, revealing a mechanism whereby a neurofibromin/Ras/MEK pathway regulates a critical CIN developmental milestone.

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