Single-Cell Multiomic Approaches Reveal Diverse Labeling of the Nervous System by Common Cre-Drivers

Keuls, Rachel A.; Parchem, Ronald J.

doi:10.3389/fncel.2021.648570

Cited by 5 publications

(3 citation statements)

References 39 publications

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“…We did not use Wnt1-Cre for neural crest-specific mutation because it is active in a significant part of the brain in addition to the neural crest ( Danielian et al, 1998 ; Keuls and Parchem, 2021 ). The Wnt1-Cre domain in the brain extensively overlaps with Lmx1b expression along the dorsal midline and in the midbrain ( Guo et al, 2007 ; Mishima et al, 2009 ).…”

Section: Resultsmentioning

confidence: 99%

Lineage-specific mutation of Lmx1b provides new insights into distinct regulation of suture development in different areas of the calvaria

Cabrera Pereira,

Dasgupta,

et al. 2023

Front. Physiol.

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The calvaria (top part of the skull) is made of pieces of bone as well as multiple soft tissue joints called sutures. The latter is crucial to the growth and morphogenesis of the skull, and thus a loss of calvarial sutures can lead to severe congenital defects in humans. During embryogenesis, the calvaria develops from the cranial mesenchyme covering the brain, which contains cells originating from the neural crest and the mesoderm. While the mechanism that patterns the cranial mesenchyme into bone and sutures is not well understood, function of Lmx1b, a gene encoding a LIM-domain homeodomain transcription factor, plays a key role in this process. In the current study, we investigated a difference in the function of Lmx1b in different parts of the calvaria using neural crest-specific and mesoderm-specific Lmx1b mutants. We found that Lmx1b was obligatory for development of the interfrontal suture and the anterior fontanel along the dorsal midline of the skull, but not for the posterior fontanel over the midbrain. Also, Lmx1b mutation in the neural crest-derived mesenchyme, but not the mesoderm-derived mesenchyme, had a non-cell autonomous effect on coronal suture development. Furthermore, overexpression of Lmx1b in the neural crest lineage had different effects on the position of the coronal suture on the apical part and the basal part. Other unexpected phenotypes of Lmx1b mutants led to an additional finding that the coronal suture and the sagittal suture are of dual embryonic origin. Together, our data reveal a remarkable level of regional specificity in regulation of calvarial development.

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Section: Resultsmentioning

confidence: 99%

Lineage-specific mutation of Lmx1b provides new insights into distinct regulation of suture development in different areas of the calvaria

Cabrera Pereira,

Dasgupta,

et al. 2023

Front. Physiol.

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“…We have revisited this issue using Sox10-Cre ( Matsuoka et al, 2005 ) and Wnt1-Cre2 ( Lewis et al, 2013 ) drivers, a nuclear-localized histone H2B-GFP reporter ( R26-LSL-tdT-2A-H2BGFP ; Wang et al, 2018 ), and immunostaining for the iris cell-type-specific transcription factors characterized in this study ( Figure 9 and Figure 9—figure supplement 1 ). Sox10-Cre labels migratory neural crest cells and Wnt1-Cre2 labels multiple cells within the embryonic CNS, including premigratory neural crest ( Debbache et al, 2018 ; Keuls and Parchem, 2021 ). For each Cre driver line, the fraction of cells of a given type that expressed the H2B-GFP reporter was determined from iris flat mounts and is summarized in Figure 9A .…”

Section: Resultsmentioning

confidence: 99%

A transcriptome atlas of the mouse iris at single-cell resolution defines cell types and the genomic response to pupil dilation

Wang

Rattner

Nathans

2021

eLife

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The iris controls the level of retinal illumination by controlling pupil diameter. It is a site of diverse ophthalmologic diseases and it is a potential source of cells for ocular auto-transplantation. The present study provides foundational data on the mouse iris based on single nucleus RNA sequencing. More specifically, this work has (1) defined all of the major cell types in the mouse iris and ciliary body, (2) led to the discovery of two types of iris stromal cells and two types of iris sphincter cells, (3) revealed the differences in cell type-specific transcriptomes in the resting vs. dilated states, and (4) identified and validated antibody and in situ hybridization probes that can be used to visualize the major iris cell types. By immunostaining for specific iris cell types, we have observed and quantified distortions in nuclear morphology associated with iris dilation and clarified the neural crest contribution to the iris by showing that Wnt1-Cre-expressing progenitors contribute to nearly all iris cell types, whereas Sox10-Cre-expressing progenitors contribute only to stromal cells. This work should be useful as a point of reference for investigations of iris development, disease, and pharmacology, for the isolation and propagation of defined iris cell types, and for iris cell engineering and transplantation.

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“…The Cre/LoxP system is a powerful tool to establish transgenic mouse lines to study gene function and generate animal models for human diseases, including cardiac diseases, cancer and many others [ 1 , 2 , 3 , 4 ]. Cre recombinase derived from bacteriophage P1 can catalyze homologous recombination between engineered loxP sites [ 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Cardiac-Specific Expression of Cre Recombinase Leads to Age-Related Cardiac Dysfunction Associated with Tumor-like Growth of Atrial Cardiomyocyte and Ventricular Fibrosis and Ferroptosis

Duan

Cui

et al. 2023

IJMS

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Transgenic expression of Cre recombinase driven by a specific promoter is normally used to conditionally knockout a gene in a tissue- or cell-type-specific manner. In αMHC-Cre transgenic mouse model, expression of Cre recombinase is controlled by the myocardial-specific α-myosin heavy chain (αMHC) promoter, which is commonly used to edit myocardial-specific genes. Toxic effects of Cre expression have been reported, including intro-chromosome rearrangements, micronuclei formation and other forms of DNA damage, and cardiomyopathy was observed in cardiac-specific Cre transgenic mice. However, mechanisms associated with Cardiotoxicity of Cre remain poorly understood. In our study, our data unveiled that αMHC-Cre mice developed arrhythmias and died after six months progressively, and none of them survived more than one year. Histopathological examination showed that αMHC-Cre mice had aberrant proliferation of tumor-like tissue in the atrial chamber extended from and vacuolation of ventricular myocytes. Furthermore, the αMHC-Cre mice developed severe cardiac interstitial and perivascular fibrosis, accompanied by significant increase of expression levels of MMP-2 and MMP-9 in the cardiac atrium and ventricular. Moreover, cardiac-specific expression of Cre led to disintegration of the intercalated disc, along with altered proteins expression of the disc and calcium-handling abnormality. Comprehensively, we identified that the ferroptosis signaling pathway is involved in heart failure caused by cardiac-specific expression of Cre, on which oxidative stress results in cytoplasmic vacuole accumulation of lipid peroxidation on the myocardial cell membrane. Taken together, these results revealed that cardiac-specific expression of Cre recombinase can lead to atrial mesenchymal tumor-like growth in the mice, which causes cardiac dysfunction, including cardiac fibrosis, reduction of the intercalated disc and cardiomyocytes ferroptosis at the age older than six months in mice. Our study suggests that αMHC-Cre mouse models are effective in young mice, but not in old mice. Researchers need to be particularly careful when using αMHC-Cre mouse model to interpret those phenotypic impacts of gene responses. As the Cre-associated cardiac pathology matched mostly to that of the patients, the model could also be employed for investigating age-related cardiac dysfunction.

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Single-Cell Multiomic Approaches Reveal Diverse Labeling of the Nervous System by Common Cre-Drivers

Cited by 5 publications

References 39 publications

Lineage-specific mutation of Lmx1b provides new insights into distinct regulation of suture development in different areas of the calvaria

Lineage-specific mutation of Lmx1b provides new insights into distinct regulation of suture development in different areas of the calvaria

A transcriptome atlas of the mouse iris at single-cell resolution defines cell types and the genomic response to pupil dilation

Cardiac-Specific Expression of Cre Recombinase Leads to Age-Related Cardiac Dysfunction Associated with Tumor-like Growth of Atrial Cardiomyocyte and Ventricular Fibrosis and Ferroptosis

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