Summary The mammalian telencephalon plays critical roles in cognition, motor function, and emotion. While many of the genes required for its development have been identified, the distant-acting regulatory sequences orchestrating their in vivo expression are mostly unknown. Here we describe a digital atlas of in vivo enhancers active in subregions of the developing telencephalon. We identified over 4,600 candidate embryonic forebrain enhancers and studied the in vivo activity of 329 of these sequences in transgenic mouse embryos. We generated serial sets of histological brain sections for 145 reproducible forebrain enhancers, resulting in a publicly accessible web-based data collection comprising over 32,000 sections. We also used epigenomic analysis of human and mouse cortex tissue to directly compare the genome-wide enhancer architecture in these species. These data provide a primary resource for investigating gene regulatory mechanisms of telencephalon development and enable studies of the role of distant-acting enhancers in neurodevelopmental disorders.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are photoreceptors of the mammalian eye that drive pupillary responses, synchronization of circadian rhythms, and other reflexive responses to daylight. Melanopsin is the ipRGC photopigment, but the signaling cascade through which this invertebrate-like opsin triggers the photocurrent in these cells is unknown. Here, using patch-clamp recordings from dissociated ipRGCs in culture, we show that a membrane-associated phosphoinositide cascade lies at the heart of the ipRGC phototransduction mechanism, similar to the cascade in rhabdomeric photoreceptors of invertebrate eyes. When ipRGCs were illuminated, melanopsin activated a G protein of the G(q/11) class, stimulating the effector enzyme phospholipase C. The presence of these signaling components in ipRGCs was confirmed by single-cell RT-PCR and immunofluorescence. The photoresponse was fully functional in excised inside-out patches of ipRGC membrane, indicating that all core signaling components are within or tightly coupled to the plasma membrane. The striking similarity of phototransduction in ipRGCs and invertebrate rhabdomeric photoreceptors reinforces the emerging view that these cells have a common evolutionary origin.

SUMMARY Elucidating the genetic control of cerebral cortical (pallial) development is essential for understanding function, evolution, and disorders of the brain. Transcription factors (TFs) that embryonically regulate pallial regionalization are expressed in gradients, raising the question of how discrete domains are generated. We provide evidence that small enhancer elements active in protodomains integrate broad transcriptional information. CreERT2 and GFP expression from 14 different enhancer elements in stable transgenic mice allowed us to define the first comprehensive regional fate map of the pallium. We explored transcriptional mechanisms that control the activity of the enhancers using informatics, in vivo occupancy by TFs that regulate cortical patterning (CoupTFI, Pax6 and Pbx1), and analysis of enhancer activity in Pax6 mutants. Overall, the results provide novel insights into how broadly expressed patterning TFs regulate the activity of small enhancer elements that drive gene expression in pallial protodomains that fate map to distinct cortical regions.

The forebrain is the seat of higher order brain functions, and many human neuropsychiatric disorders are due to genetic defects affecting forebrain development, making it imperative to understand the underlying genetic circuitry. Recent progress now makes it possible to begin fully elucidating the genomic regulatory mechanisms that control forebrain gene expression. Herein, we discuss the current knowledge of how transcription factors drive gene expression programs through their interactions with cis-acting genomic elements, such as enhancers; how analyses of chromatin and DNA modifications provide insights into gene expression states; and how these approaches yield insights into the evolution of the human brain.

SUMMARY Elucidating the transcriptional circuitry controlling forebrain development requires an understanding of enhancer activity and regulation. We generated stable transgenic mouse lines that express CreERT2 and GFP from 10 different enhancer elements with activity in distinct domains within the embryonic basal ganglia. We used these unique tools to generate a comprehensive regional fate map of the mouse subpallium including sources for specific subtypes of amygdala neurons. We then focused on deciphering transcriptional mechanisms that control enhancer activity. Using machine learning computations, in vivo chromosomal occupancy of 13 transcription factors that regulate subpallial patterning and differentiation, and analysis of enhancer activity in Dlx1/2 and Lhx6 mutants, we elucidated novel molecular mechanisms that regulate region-specific enhancer activity in the developing brain. Thus, these subpallial enhancer transgenic lines are data and tool resources to study transcriptional regulation of GABAergic cell fate.

The prefrontal cortex (PFC) and its connections with the mediodorsal thalamus are crucial for cognitive flexibility and working memory 1 and are thought to be altered in disorders such as autism 2,3 and schizophrenia 4,5 . Although developmental mechanisms that govern the regional patterning of the cerebral cortex have been characterized in rodents [6][7][8][9] , the mechanisms that underlie the development of PFCmediodorsal thalamus connectivity and the lateral expansion of the PFC with a distinct granular layer 4 in primates 10,11 remain unknown. Here we report an anterior (frontal) to posterior (temporal), PFC-enriched gradient of retinoic acid, a signalling molecule that regulates neural development and function [12][13][14][15] , and we identify genes that are regulated by retinoic acid in the neocortex of humans and macaques at the early and middle stages of fetal development. We observed several potential sources of retinoic acid, including the expression and cortical expansion of retinoic-acid-synthesizing enzymes specifically in primates as compared to mice. Furthermore, retinoic acid signalling is largely confined to the prospective PFC by CYP26B1, a retinoic-acid-catabolizing enzyme, which is upregulated in the prospective motor cortex. Genetic deletions in mice revealed that retinoic acid signalling through the retinoic acid receptors RXRG and RARB, as well as CYP26B1-dependent catabolism, are involved in proper molecular patterning of prefrontal and motor areas, development of PFC-mediodorsal thalamus connectivity, intra-PFC dendritic spinogenesis and expression of the layer 4 marker RORB. Together, these findings show that retinoic acid signalling has a critical role in the development of the PFC and, potentially, in its evolutionary expansion.The PFC reaches its greatest complexity in anthropoid primates (monkeys and apes), which appear to uniquely have many prefrontal areas that cover the entire anterior two-thirds of the frontal lobe and a well-defined granular layer 4 10,11 . Previous analyses revealed that the transcriptomic differences between neocortical areas are most prominent in primates during the middle stages of fetal development, corresponding to post-conception weeks (PCW) 13 to 24 (hereafter referred to as 'mid-fetal') 16,17 -a crucial period for neuronal specification and the initial assembly of neocortical neural circuits 18 . Thus, we hypothesized that the molecular processes that govern the development and evolutionary diversification of the PFC could be revealed by differential regional gene expression analysis of the primate mid-fetal neocortex. Fetal frontal upregulation of RA-related genesUsing human BrainSpan RNA-sequencing (RNA-seq) data 17 , we screened for genes that are differentially upregulated in the mid-fetal frontal lobe. The mid-fetal data consisted of tissue-level samples ranging in age from PCW 16 to 22, which included four prospective PFC areas (medial, mPFC or MFC; orbital, oPFC or OFC; dorsolateral, dlPFC or DFC; and ventrolateral, vlPFC or VFC) and the primar...

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