Transcriptional Analysis of Gli3 Mutants Identifies Wnt Target Genes in the Developing Hippocampus

Hasenpusch‐Theil, Kerstin; Magnani, Dario; Amaniti, Eleni-Maria; Lin, Han; Armstrong, J. Douglas; Theil, Thomas

doi:10.1093/cercor/bhr365

Cited by 49 publications

(59 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Slices were cultured for 24 h in the presence of DMSO or various concentration of Chir, which selectively inhibits GSK3β and therefore activates Wnt signaling, and processed for ISH for Dmrt5 and Axin2 as a positive control. As previously reported, Axin2 was induced by Chir and at the highest dose was expressed through the whole telencephalic ventricular zone (Hasenpusch-Theil et al 2012) (Fig. 8A-D).…”

Section: Activation Of Wnt/β-catenin Signaling Induces Dmrt5 Expressionsupporting

confidence: 86%

“…In this way, a robust positive feedback loop is established in the caudomedial cortex contributing to reinforcing Emx2 expression (Mallamaci 2011). Gli3 controls Wnt gene expression which in turn activates its expression and induces several Wnt targets, including direct targets such as Emx2 and Dmrt3 (Theil et al 1999(Theil et al , 2002Fotaki et al 2011;Hasenpusch-Theil et al 2012). Our data show that Dmrt5 which is required for Wnt gene expression in the midline is regulated by Wnt and that Gli3 is required at least for the maintenance of Dmrt5 in the forebrain.…”

Section: Roles For Dmrt5 In the Gene Network Regulating Early Caudomementioning

confidence: 54%

“…4E,F). Several modulators including Axin2 which is upregulated in the area of strong canonical Wnt signaling (Jho et al 2002) and Rspo1-3 strongly expressed in the CH (Hasenpusch-Theil et al 2012) were also reduced in Dmrt5 −/− embryos. The remaining Rspo1-3 signal detected in the caudal telencephalon of the mutants likely corresponds to the signal detected in the eminentia thalami in the controls (Fig.…”

Section: Reduction Of Wnt and Bmp Signals In The Caudomedial Cortex Amentioning

confidence: 95%

“…When Lhx2 is deleted later, between E10.5 and E11.5, lateral cortical progenitors generate olfactory cortex rather than lateral neocortex (Chou et al 2009). Genes encoding the homeodomain transcription factor Cux2, the orphan nuclear receptor Nurr1/Nr4A2, Nfib, and Dmrt3 are recently identified Wnt targets that show restricted expression in the dorsomedial telencephalon and may thus also function in early cortical regionalization (Hasenpusch-Theil et al 2012). Given the deficiency of Wnt and Bmp in the caudomedial part of the telencephalon of Dmrt5 mutants, we suspected that expression of those genes would be altered and examined their expression by ISH at E12.5.…”

Section: Altered Expression Of Transcriptional Regulators Of Corticalmentioning

confidence: 99%

See 3 more Smart Citations

The Doublesex Homolog Dmrt5 is Required for the Development of the Caudomedial Cerebral Cortex in Mammals

et al. 2012

Self Cite

View full text Add to dashboard Cite

Regional patterning of the cerebral cortex is initiated by morphogens secreted by patterning centers that establish graded expression of transcription factors within cortical progenitors. Here, we show that Dmrt5 is expressed in cortical progenitors in a high-caudomedial to low-rostrolateral gradient. In its absence, the cortex is strongly reduced and exhibits severe abnormalities, including agenesis of the hippocampus and choroid plexus and defects in commissural and thalamocortical tracts. Loss of Dmrt5 results in decreased Wnt and Bmp in one of the major telencephalic patterning centers, the dorsomedial telencephalon, and in a reduction of Cajal-Retzius cells. Expression of the dorsal midline signaling center-dependent transcription factors is downregulated, including Emx2, which promotes caudomedial fates, while the rostral determinant Pax6, which is inhibited by midline signals, is upregulated. Consistently, Dmrt5 −/− brains exhibit patterning defects with a dramatic reduction of the caudomedial cortex. Dmrt5 is increased upon the activation of Wnt signaling and downregulated in Gli3 xt/xt mutants. We conclude that Dmrt5 is a novel Wnt-dependent transcription factor required for early cortical development and that it may regulate initial cortical patterning by promoting dorsal midline signaling center formation and thereby helping to establish the graded expression of the other transcription regulators of cortical identity.

show abstract

Section: Activation Of Wnt/β-catenin Signaling Induces Dmrt5 Expressionsupporting

confidence: 86%

Section: Roles For Dmrt5 In the Gene Network Regulating Early Caudomementioning

confidence: 54%

Section: Reduction Of Wnt and Bmp Signals In The Caudomedial Cortex Amentioning

confidence: 95%

Section: Altered Expression Of Transcriptional Regulators Of Corticalmentioning

confidence: 99%

See 2 more Smart Citations

The Doublesex Homolog Dmrt5 is Required for the Development of the Caudomedial Cerebral Cortex in Mammals

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recent studies demonstrate that canonical WNT signaling increases expression of Dmrt3 and Dmrta2, associated with cortical patterning (Hasenpusch-Theil et al, 2012;Kikkawa et al, 2013;Konno et al, 2012;Saulnier et al, 2012). Dmrta2, Dmrt3 and Emx2 maintain regulatory interactions, with Dmrta2 an upstream regulator of Emx2 expression (Saulnier et al, 2012).…”

Section: Patterning Interactions Among Dmrt Genes Emx2 and Wntsmentioning

confidence: 99%

The cortical hem regulates the size and patterning of neocortex

et al. 2014

View full text Add to dashboard Cite

The cortical hem, a source of Wingless-related (WNT) and bone morphogenetic protein (BMP) signaling in the dorsomedial telencephalon, is the embryonic organizer for the hippocampus. Whether the hem is a major regulator of cortical patterning outside the hippocampus has not been investigated. We examined regional organization across the entire cerebral cortex in mice genetically engineered to lack the hem. Indicating that the hem regulates dorsoventral patterning in the cortical hemisphere, the neocortex, particularly dorsomedial neocortex, was reduced in size in latestage hem-ablated embryos, whereas cortex ventrolateral to the neocortex expanded dorsally. Unexpectedly, hem ablation also perturbed regional patterning along the rostrocaudal axis of neocortex. Rostral neocortical domains identified by characteristic gene expression were expanded, and caudal domains diminished. A similar shift occurs when fibroblast growth factor (FGF) 8 is increased at the rostral telencephalic organizer, yet the FGF8 source was unchanged in hem-ablated brains. Rather we found that hem WNT or BMP signals, or both, have opposite effects to those of FGF8 in regulating transcription factors that control the size and position of neocortical areas. When the hem is ablated a necessary balance is perturbed, and cerebral cortex is rostralized. Our findings reveal a much broader role for the hem in cortical development than previously recognized, and emphasize that two major signaling centers interact antagonistically to pattern cerebral cortex.

show abstract

Hypothesis: The female excess in cranial neural tube defects reflects an epigenetic drag of the inactivating x chromosome on the molecular mechanisms of neural fold elevation

Juriloff

Harris

2012

Birth Defects Research

View full text Add to dashboard Cite

Females have long been known to be in excess among cranial neural tube defect (NTD) cases. Up to two thirds of human anencephalics and mouse exencephalics from various genetic causes are female, but the cause of this female excess is unknown. It appears not to be attributable to gonadal hormones, developmental delay in females, or preferential death of affected males. Recent studies of the Trp53 mouse mutant showed that exencephaly susceptibility depends on the presence of two X chromosomes, not the absence of the Y. Over a decade ago, we hypothesized that the relevant difference between female and male mammalian embryos at the time of cranial neural tube closure is the fact that females methylate most of the DNA in the large inactive X chromosome after every cell division, reducing the methylation available for other needs in female cells. Recently, the Whitelaw laboratory identified several proteins in mice (Momme D genes) involved in epigenetic silencing and methylation and shared in the silencing of transgenes, retrotransposons, and the inactive-X, and suggested that the inactive-X acts as a "sink" for epigenetic silencing proteins. The "inactive-X sink" hypothesis can be used to suggest expected changes in sex ratio in cranial NTDs in response to various genetic or environmental alterations. We recommend that observation of sex ratio become a standard component of all NTD studies. We suggest that the female excess among cranial NTDs is an epigenetic phenomenon whose molecular investigation will produce insight into the mechanisms underlying NTDs.

show abstract

Transcriptional Analysis of Gli3 Mutants Identifies Wnt Target Genes in the Developing Hippocampus

Cited by 49 publications

References 74 publications

The Doublesex Homolog Dmrt5 is Required for the Development of the Caudomedial Cerebral Cortex in Mammals

The Doublesex Homolog Dmrt5 is Required for the Development of the Caudomedial Cerebral Cortex in Mammals

The cortical hem regulates the size and patterning of neocortex

Hypothesis: The female excess in cranial neural tube defects reflects an epigenetic drag of the inactivating x chromosome on the molecular mechanisms of neural fold elevation

Contact Info

Product

Resources

About