A suite of transgenic driver and reporter mouse lines with enhanced brain cell type targeting and functionality

Daigle, Tanya L.; Madisen, Linda; Hage, Travis A.; Valley, Matthew T.; Knoblich, Ulf; Larsen, Rylan S.; Takeno, Marc; Huang, Lawrence; Gu, Hongcang; Larsen, Rachael; Mills, Maya; Bosma-Moody, Alice; Siverts, La’ Akea; Walker, Miranda; Graybuck, Lucas T.; Yao, Zizhen; Fong, Olivia; Garren, Emma; Lenz, Garreck H.; Chavarha, Mariya; Pendergraft, Julie; Harrington, James; Hirokawa, Karla E.; Harris, Julie A.; McGraw, Mary; Ollerenshaw, Douglas R.; Smith, Kimberly A.; Baker, Baker A; Ting, Jonathan T.; Sunkin, Susan M.; Lecoq, Jérôme; Lin, Michael Z.; Boyden, Edward S.; Murphy, Gabe J.; Costa, Nuno da; Waters, Jack; Li, Lü; Tasic, Bosiljka; Zeng, Hongkui

doi:10.1101/224881

Cited by 68 publications

(98 citation statements)

References 68 publications

(94 reference statements)

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“…Foxp2-ires-Cre (Jax 030541), Nkx2.1-ires-Flp (Jax 028577), Npas1-Cre-tdTomato BAC (Jax 027718), PV-ires-Cre (Jax 017320), PV-2A-Flp (Jax 022730), PV-tdTomato BAC (Jax 027395). FSF-tdTomato (Ai65F) was generated as previously described (Daigle et al, 2018;Yetman et al, 2019). In brief, FSF-LSL-40 tdTomato was crossed with EIIa-Cre (Jax 003724) to delete the LSL cassette.…”

Section: Micementioning

confidence: 99%

Npas1⁺-Nkx2.1⁺Neurons Are an Integral Part of the Cortico-pallido-cortical Loop

Abecassis¹,

Berceau²,

Win³

et al. 2019

Preprint

108

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Within the basal ganglia circuit, the external globus pallidus (GPe) is critically involved in motor control. Aside from Foxp2+ neurons and ChAT+ neurons that have been established as unique neuron types, there is little consensus on the classification of GPe neurons. Properties of the remaining neuron types are poorly-defined. In this study, we leverage new mouse lines, viral tools, and molecular markers to better define GPe neuron subtypes. We found that Sox6 represents a novel, defining marker for GPe neuron subtypes. Lhx6+ neurons that lack the expression of Sox6 were devoid of both parvalbumin and Npas1. This result confirms previous assertions of the existence of a unique Lhx6+ population. Neurons that arise from the Dbx1+ lineage were similarly abundant in the GPe and displayed a heterogeneous makeup. Importantly, tracing experiments revealed that Npas1+-Nkx2.1+ neurons represent the principal non-cholinergic, cortically-projecting neurons. In other words, they form the pallido-cortical arm of the cortico-pallido-cortical loop. Our data further described that pyramidal-tract neurons in the cortex collateralized within the GPe, forming a closed-loop system between the two brain structures. Overall, our findings reconcile some of the discrepancies that arose from differences in techniques or the reliance on pre-existing tools. While spatial distribution and electrophysiological properties of GPe neurons reaffirm the diversification of GPe subtypes, statistical analyses strongly support the notion that these neuron subtypes can be categorized under the two principal neuron classes—i.e., PV+ neurons and Npas1+ neurons.Significance statementThe poor understanding of the neuronal composition in the GPe undermines our ability to interrogate its precise behavioral and disease involvements. In this study, twelve different genetic crosses were used, hundreds of neurons were electrophysiologically-characterized, and over 100,000 neurons were histologically- and/or anatomically-profiled. Our current study further establishes the segregation of GPe neuron classes and illustrates the complexity of GPe neurons in adult mice. Our results support the idea that Npas1+-Nkx2.1+ neurons are a distinct GPe neuron subclass. By providing a detailed analysis of the organization of the cortico-pallidal-cortical projection, our findings establish the cellular and circuit substrates that can be important for motor function and dysfunction.

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Section: Micementioning

confidence: 99%

Npas1⁺-Nkx2.1⁺Neurons Are an Integral Part of the Cortico-pallido-cortical Loop

Abecassis¹,

Berceau²,

Win³

et al. 2019

Preprint

108

View full text Add to dashboard Cite

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“…Because steroid hormone receptors are expressed only in a subpopulation of cells within sexually dimorphic brain regions, it is critical to isolate specific cell types prior to downstream genomics assays. Cell-type targeting has been made possible with Cre-loxP and Flp-FRT recombination systems, which rely on cell-type-specific active gene promoters to facilitate knockin-knockout expression of fluorescent reporter or molecular-tagging alleles (Daigle et al, 2018;Tsien et al, 1996). When Cre and Flp animals are crossed, cells co-expressing two driver genes may be labeled, allowing for more refined targeting .…”

Section: Gonadal Steroid Hormones Direct Sexual Differentiation Of mentioning

confidence: 99%

Signatures of sex: Sex differences in gene expression in the vertebrate brain

Gegenhuber

Tollkühn

2019

WIREs Developmental Biology

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Women and men differ in disease prevalence, symptoms, and progression rates for many psychiatric and neurological disorders. As more preclinical studies include both sexes in experimental design, an increasing number of sex differences in physiology and behavior have been reported. In the brain, sex‐typical behaviors are thought to result from sex‐specific patterns of neural activity in response to the same sensory stimulus or context. These differential firing patterns likely arise as a consequence of underlying anatomic or molecular sex differences. Accordingly, gene expression in the brains of females and males has been extensively investigated, with the goal of identifying biological pathways that specify or modulate sex differences in brain function. However, there is surprisingly little consensus on sex‐biased genes across studies and only a handful of robust candidates have been pursued in the follow‐up experiments. Furthermore, it is not known how or when sex‐biased gene expression originates, as few studies have been performed in the developing brain. Here we integrate molecular genetic and neural circuit perspectives to provide a conceptual framework of how sex differences in gene expression can arise in the brain. We detail mechanisms of gene regulation by steroid hormones, highlight landmark studies in rodents and humans, identify emerging themes, and offer recommendations for future research. This article is categorized under: Nervous System Development > Vertebrates: General Principles Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms Gene Expression and Transcriptional Hierarchies > Sex Determination

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“…We found that the percentage of endocardial cells expressing tdTomato was significantly higher in Npr3-sCreER;R26-LZLT than Npr3-CreER;R26-LZLT ( Fig 3C-E). Additionally, we crossed Npr3-sCreER or Npr3-CreER with R26-GFP reporter (Daigle et al, 2018;Zhao et al, 2018) and found that Npr3-sCreER was far more efficient in recombining R26-GFP than Npr3-CreER (Appendix Fig S6). Taken together, the above data demonstrated that sCreER was more efficient than CreER in recombination of a refractory target locus.…”

Section: Of 12mentioning

confidence: 99%

Generation of a self‐cleaved inducible Cre recombinase for efficient temporal genetic manipulation

Tian

Liu

et al. 2020

The EMBO Journal

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Site‐specific recombinase‐mediated genetic technology, such as inducible Cre‐loxP recombination (CreER), is widely used for in vivo genetic manipulation with temporal control. The Cre‐loxP technology improves our understanding on the in vivo function of specific genes in organ development, tissue regeneration, and disease progression. However, inducible CreER often remains inefficient in gene deletion. In order to improve the efficiency of gene manipulation, we generated a self‐cleaved inducible CreER (sCreER) that switches inducible CreER into a constitutively active Cre by itself. We generated endocardial driver Npr3‐sCreER and fibroblast driver Col1a2‐sCreER, and compared them with conventional Npr3‐CreER and Col1a2‐CreER, respectively. For easy‐to‐recombine alleles such as R26‐tdTomato, there was no significant difference in recombination efficiency between sCreER and the conventional CreER. However, for alleles that were relatively inert for recombination such as R26‐Confetti, R26‐LZLT, R26‐GFP, or VEGFR2flox/flox alleles, sCreER showed a significantly higher efficiency in recombination compared with conventional CreER in endocardial cells or fibroblasts. Compared with conventional CreER, sCreER significantly enhances the efficiency of recombination to induce gene expression or gene deletion, allowing temporal yet effective in vivo genomic modification for studying gene function in specific cell lineages.

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A suite of transgenic driver and reporter mouse lines with enhanced brain cell type targeting and functionality

Cited by 68 publications

References 68 publications

Npas1⁺-Nkx2.1⁺Neurons Are an Integral Part of the Cortico-pallido-cortical Loop

Npas1⁺-Nkx2.1⁺Neurons Are an Integral Part of the Cortico-pallido-cortical Loop

Signatures of sex: Sex differences in gene expression in the vertebrate brain

Generation of a self‐cleaved inducible Cre recombinase for efficient temporal genetic manipulation

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A suite of transgenic driver and reporter mouse lines with enhanced brain cell type targeting and functionality

Cited by 68 publications

References 68 publications

Npas1+-Nkx2.1+Neurons Are an Integral Part of the Cortico-pallido-cortical Loop

Npas1+-Nkx2.1+Neurons Are an Integral Part of the Cortico-pallido-cortical Loop

Signatures of sex: Sex differences in gene expression in the vertebrate brain

Generation of a self‐cleaved inducible Cre recombinase for efficient temporal genetic manipulation

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Product

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Npas1⁺-Nkx2.1⁺Neurons Are an Integral Part of the Cortico-pallido-cortical Loop

Npas1⁺-Nkx2.1⁺Neurons Are an Integral Part of the Cortico-pallido-cortical Loop