New Mouse Lines for the Analysis of Neuronal Morphology Using CreER(T)/loxP-Directed Sparse Labeling

Badea, Tudor C.; Hua, Zhong L.; Smallwood, Phillip M.; Williams, John; Rotolo, Thomas; Ye, Xin; Nathans, Jeremy

doi:10.1371/journal.pone.0007859

Cited by 87 publications

(95 citation statements)

References 50 publications

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“…As shown in Fig. 1E, we developed three distinct animal models for the studies reported here by breeding these E3= F/F Ed Ϫ/Ϫ mice with either germ line-expressing Cre mice (28) or with tamoxifen-inducible Cre mice (22) or with mice specifically expressing Cre in mature B cells (23). Successful deletion of E3= in each of these cases generates E3=…”

Section: Resultsmentioning

confidence: 99%

“…As our initial approach to test for the importance of the Ig gene's downstream enhancers on continued gene expression following their deletion, we bred E3= F/F Ed Ϫ/Ϫ mice with those harboring a tamoxifen-inducible Cre [ROSA26CreER(T) (22)] to obtain a homozygous E3= F/F Ed Ϫ/Ϫ ROSA26CreER(T) line. It is known that the lifetime of splenic mature B cells can be from several weeks to months (29), so we sought to delete E3= in such nonreplicating mature B cells for the subsequent analysis of Ig gene expression in these cells.…”

Section: Resultsmentioning

confidence: 99%

“…Tamoxifen-inducible Cre mice, named ROSA26CreER(T) (22), were purchased from The Jackson Laboratory (stock no. 004847).…”

Section: Methodsmentioning

confidence: 99%

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Loss of an Igκ Gene Enhancer in Mature B Cells Results in Rapid Gene Silencing and Partial Reversible Dedifferentiation

Zhou

Xiang

Ding

et al. 2013

Molecular and Cellular Biology

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bWe address here whether there is cellular memory of a transcriptional enhancer once it has served its purpose to establish an active chromatin state. We have previously shown that the mouse Ig gene's downstream enhancers, E3= and Ed, are essential but play redundant roles for establishing transcriptional activity in the locus during B cell development. To determine whether these enhancers are also necessary for the maintenance of transcriptional activity, we conditionally deleted E3= in mature B cells that possessed Ed ؊/؊ alleles. Upon E3= deletion, the locus became rapidly silenced and lost positive histone epigenetic marks, and the mature B cells partially dedifferentiated, induced RAG-1 and -2 along with certain other pro-B cell makers, and then redifferentiated after triggering Ig gene rearrangements. We conclude that the Ig gene's downstream enhancers are essential for both the establishment and maintenance of transcriptional activity and that there is no cellular memory of previous transcriptional activity in this locus. Furthermore, upon enhancer loss, the mature B cells unexpectedly underwent reversible retrograde differentiation. This result establishes that receptor editing can occur in mature B cells and raises the possibility that this may provide a tolerance mechanism for eliminating autoreactive B cells in the periphery. During B cell development, the mouse IgH and IgL loci become activated in a stepwise fashion for gene rearrangement (1). The IgH gene rearranges first, by sequential D-J and then by V-(D)J joining, leading to the pro-and pre-B cell stages of development, respectively. The Ig locus undergoes rearrangement next in pre-B cells, where a V gene is joined to a J region. If Ig V-J joining is productively unsuccessful because of out-of-reading frame recombination junctions, then the Ig locus becomes activated for rearrangement and expression, which in wild-type (WT) mice accounts for production of only approximately 5% of the total IgL chains (2).In order to characterize chromatin structure-function relationships in a model system, research in our laboratory has focused on the mouse Ig locus because it offers the opportunity to identify changes in chromatin structure that may precede gene rearrangement and transcriptional activation during B lymphocyte differentiation, as well as to visualize chromatin remodeling events that are linked to gene activation (reference 3 and references therein). Rearrangement of the Ig locus deposits a V gene carrying its own promoter into a chromatin domain containing three powerful enhancers: an intronic enhancer (Ei) within the transcription unit (4), and two enhancers downstream of the transcription termination region, termed E3= and Ed (3, 5). The results of chromosome conformation capture experiments have revealed that in activated B cells, the three enhancers exhibit all possible pairwise interactions with themselves and rearranged V gene promoters, with the looping out of the intervening DNA sequences (6). However, in unstimulated B cells, rearranged...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Loss of an Igκ Gene Enhancer in Mature B Cells Results in Rapid Gene Silencing and Partial Reversible Dedifferentiation

Zhou

Xiang

Ding

et al. 2013

Molecular and Cellular Biology

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“…Fig. 1 compares the brain defects in Fz3 −/− mice visualized by NF immunostaining with the trajectories of dorsal thalamic axons visualized with a RORα-IRES-Cre knock-in allele and a Cre-controlled human placental alkaline phosphatase (hPLAP; hereafter "AP") reporter, R26iAP (10,11). In the prenatal mouse brain, RORα is expressed in the dorsal thalamus (12).…”

Section: Significancementioning

confidence: 99%

Frizzled3 is required for the development of multiple axon tracts in the mouse central nervous system

Hua¹,

Jeon

Caterina

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Targeted mutation of the Frizzled3 (Fz3) gene in mice has been shown to disrupt the growth and guidance of a subset of peripheral and central axons. Here we used conditional deletion of Fz3 to explore the forebrain territories in which Fz3 action is required for the development of the anterior commissure and the corticothalamic, corticospinal, and thalamocortical tracts. Experiments with regionspecific deletion of Fz3 using a variety of Cre lines show that proper routing of corticothalamic and thalamocortical axons in the internal capsule requires Fz3 expression in the ventral telencephalon. The pattern of defects among forebrain axon tracts that are induced by conditional deletion of Fz3 conforms closely to the pattern previously observed with analogous conditional deletion of Celsr3, implying a close mechanistic link between Fz3 and Celsr3 in axon guidance. We further found that several central nervous system axon tracts require Fz3 function as early as embryonic day 11.5, and that Fz3 is required for pathfinding by dopaminergic and serotonergic axons in the brain and by a subset of optic tract axons. In addition, conditional deletion of Fz3 in all tissues caudal to the neck eliminates the spinothalamic tract and the transmission of somatosensory information from the spinal cord to the brain, as determined by neuroanatomic tracing and behavioral testing.planar cell polarity | Cre/loxP C omplexity within the mammalian nervous system can be roughly divided into two categories: cell type identity and morphology/connectivity. On its largest scale, the second category is exemplified by the many distinct patterns of long-range axonal trajectories within the adult CNS. The guidance mechanisms responsible for these axonal trajectories have been an object of longstanding interest to neurobiologists, and, over the past 20 y, a wide variety of attractive and repulsive axon guidance systems have been identified (1). For a few well-defined axon growth and guidance decisions-such as dorsal vs. ventral growth of limb motor axons and midline crossing of retinal ganglion cell (RGC) and spinal sensory axons-the roles of several guidance systems, including Slit/Robo, Ephrin/Eph, and Semaphorin/Plexin, have been intensively investigated (2, 3).One recently discovered axon growth and guidance system uses some of the same molecular components that were identified in the context of epithelial polarity determination, a process referred to as tissue polarity or planar cell polarity (PCP). As first defined in Drosophila, PCP controls polarity within the plane of the epithelium and is mediated by a small number of integral membrane or membrane-associated proteins (4). Within the responsive epithelium, several PCP proteins are localized asymmetrically within each cell in a pattern that matches the large-scale vectorial asymmetry of the epithelium. In mice, two integral membrane PCP proteins, Frizzled3 (Fz3) and Celsr3, control a nearly identical set of axon growth and guidance processes, with loss-of-function mutations in either gene pro...

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“…This project further asks for lineage data at several intermediate stages of retinogenesis, and these results will be best compared to adult clone composition in the context of a unique and consistent mouse line. There are currently other mouse lines available to achieve sparse Cremediated recombination in the retina (Badea et al, 2009b;Yun et al, 2009;Brzezinski et al, 2011). In these lines, a drug such as tamoxifen is used to activate Cre recombinase activity at a specific time, and limiting dilutions can be applied to restrict recombination to a subset of RPCs.…”

Section: Cre Recombination In Rpcsmentioning

confidence: 99%

In vivo evidence for unbiased ikaros retinal lineages using an ikaros‐cre mouse line driving clonal recombination

Tarchini

Jolicoeur

Cayouette

2012

Developmental Dynamics

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Background: We showed previously that the transcription factor Ikaros is expressed in early but not late retinal progenitors cells (RPCs), and is necessary and sufficient for the production of early-born neurons. Preliminary evidence using retinal explant cultures qualitatively suggested that Ikaros-positive RPCs might share a common lineage with Ikaros-negative RPCs. Results: To explore further this question in vivo in a quantitative manner, we generated BAC transgenic mouse lines expressing Cre recombinase under the regulatory elements of the Ikaros gene, and crossed them with Cre reporter lines. Different transgenic lines labeled a variable number of RPCs, resulting in either dense or sparse radial arrays of reporter-positive progenies. Analysis of over 800 isolated cell arrays, which are most likely clones, confirmed that Ikaros-expressing RPCs generate both early-and late-born cell types in the same lineage, and that the overall cell composition of the arrays closely resembles that of the population of the mature retina. Interestingly, another sparse line did not label arrays, but appeared to specifically reflect Ikaros postmitotic expression in amacrine and ganglion cells. Key words: lineage; competence; temporal identity; cell fate; cell specification; development Key FindingsThe Ikaros retinal lineage gives rise to both early-and late-born cell types and is confirmed unbiased in vivo One Ikaros-Cre mouse line allows sparse recombination in retinal progenitors and is validated as a tool for in vivo lineage tracing A distinct Ikaros-Cre mouse line allows sparse recombination specifically in some postmitotic early-born retinal cell types

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New Mouse Lines for the Analysis of Neuronal Morphology Using CreER(T)/loxP-Directed Sparse Labeling

Cited by 87 publications

References 50 publications

Loss of an Igκ Gene Enhancer in Mature B Cells Results in Rapid Gene Silencing and Partial Reversible Dedifferentiation

Loss of an Igκ Gene Enhancer in Mature B Cells Results in Rapid Gene Silencing and Partial Reversible Dedifferentiation

Frizzled3 is required for the development of multiple axon tracts in the mouse central nervous system

In vivo evidence for unbiased ikaros retinal lineages using an ikaros‐cre mouse line driving clonal recombination

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