<i>Patched 1</i> conditional null allele in mice

Ellis, Tammy; Smyth, Ian; Riley, Emily; Graham, Scott E.; Elliot, Kate; Narang, Monica A.; Kay, Graham F.; Wicking, Carol; Wainwright, Brandon

doi:10.1002/gene.10208

Cited by 95 publications

(94 citation statements)

References 25 publications

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“…SuFu loxP ) and Gli3 ⌬699 (Böse et al, 2002) mice were maintained on a mixed background, and SuFu ϩ/ Ϫ (kindly provided by C.-C. Hui), Hoxb.7-Cre (Zhao et al, 2004), Ptc1 ϩ/ Ϫ (Goodrich et al, 1997) and Ptc1 loxP (Ellis et al, 2003) mice were maintained on a CD1/129 background. ROSA lacZ/lacZ mice (Soriano, 1999) were maintained on a C57BL/6 background.…”

Section: Methodsmentioning

confidence: 99%

Suppressor of Fused Controls Mid-Hindbrain Patterning and Cerebellar Morphogenesis via GLI3 Repressor

Kim

Gill²,

Rotin³

et al. 2011

J. Neurosci.

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Sonic Hedgehog and its GLI transcriptional effectors control foliation complexity during cerebellar morphogenesis by promoting granule cell precursor proliferation. Here, we reveal a novel contribution of Sonic Hedgehog-GLI signaling to cerebellar patterning and cell differentiation by generating mice with targeted deletion of Suppressor of Fused (SuFu), a regulator of Sonic Hedgehog signaling, in the mid-hindbrain. Postnatal SuFu-deficient mice exhibit impaired motor coordination and severe cerebellar mispatterning. SuFu conditional knock-out embryos display abnormal mid-hindbrain morphology associated with misexpression of Fgf8, and delayed differentiation and abnormal migration of major cerebellar cell types. Sonic Hedgehog is ectopically expressed in the external granule layer and Hedgehog signaling is upregulated. While expression of full-length GLI transcriptional activators downstream of Hedgehogs is markedly reduced, a processed form of GLI3, a transcriptional repressor, is essentially lost. Genetic expression of a Gli3 allele encoding GLI3 repressor in SuFu-deficient mice largely rescues abnormal cerebellar patterning and cell differentiation observed in mice with SuFu deficiency alone. Together, our data demonstrate that SuFu controls cerebellar patterning and cell differentiation in a GLI3 repressordependent manner.

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Section: Methodsmentioning

confidence: 99%

Suppressor of Fused Controls Mid-Hindbrain Patterning and Cerebellar Morphogenesis via GLI3 Repressor

Kim

Gill²,

Rotin³

et al. 2011

J. Neurosci.

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“…Dicer1flox, Ptch1flox, and Gt(ROSA)26Sor;lacZ mice have previously been described (Soriano 1999;Ellis et al 2003;Harfe et al 2005). Atoh1-Cre mice (line 8) were generated in the Rowitch laboratory at the Institute for Regeneration Medicine (San Francisco) and are modified from Atoh1-Cre mice previously described (Schuller et al 2007).…”

Section: Micementioning

confidence: 99%

“…Alternatively, constitutive activation of Shh-Ptch signaling in granule cell precursors is well known to produce hyperplasia that resembles human medulloblastoma (Goodrich et al 1997;Pietsch et al 1997;Raffel et al 1997). In fact, the most widely used animal model for medulloblastoma is the targeted mutation of the Ptch1 gene, either heterozygous null (Goodrich et al 1997;Hahn et al 1998;Zibat et al 2009) or conditional knockouts associated with the granule neuron lineage (Ellis et al 2003;Yang et al 2008). Given that the two biological processes of hypoplasia and hyperplasia are on opposing growth spectrums, we hypothesized that the co-deregulation of miRNA biogenesis and Shh-Ptch-signaling pathways would attenuate overall growth and lead to reduced severity of murine medulloblastoma.…”

mentioning

confidence: 99%

MicroRNA Biogenesis and Hedgehog-Patched Signaling Cooperate to Regulate an Important Developmental Transition in Granule Cell Development

Constantin

Wainwright

2016

Genetics

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The Dicer1, Dcr-1 homolog (Drosophila) gene encodes a type III ribonuclease required for the canonical maturation and functioning of microRNAs (miRNAs). Subsets of miRNAs are known to regulate normal cerebellar granule cell development, in addition to the growth and progression of medulloblastoma, a neoplasm that often originates from granule cell precursors. Multiple independent studies have also demonstrated that deregulation of Sonic Hedgehog (Shh)-Patched (Ptch) signaling, through miRNAs, is causative of granule cell pathologies. In the present study, we investigated the genetic interplay between miRNA biogenesis and Shh-Ptch signaling in granule cells of the cerebellum by way of the Cre/lox recombination system in genetically engineered models of Mus musculus (mouse). We demonstrate that, although the miRNA biogenesis and Shh-Ptch-signaling pathways, respectively, regulate the opposing growth processes of cerebellar hypoplasia and hyperplasia leading to medulloblastoma, their concurrent deregulation was nonadditive and did not bring the growth phenotypes toward an expected equilibrium. Instead, mice developed either hypoplasia or medulloblastoma, but of a greater severity. Furthermore, some genotypes were bistable, whereby subsets of mice developed hypoplasia or medulloblastoma. This implies that miRNAs and Shh-Ptch signaling regulate an important developmental transition in granule cells of the cerebellum. We also conclusively show that the Dicer1 gene encodes a haploinsufficient tumor suppressor gene for Ptch1-induced medulloblastoma, with the monoallielic loss of Dicer1 more severe than biallelic loss. These findings exemplify how genetic interplay between pathways may produce nonadditive effects with a substantial and unpredictable impact on biology. Furthermore, these findings suggest that the functional dosage of Dicer1 may nonadditively influence a wide range of Shh-Ptch-dependent pathologies.

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“…Mice with a conditional allele of patched homolog 1 (Ptch1 flox/ þ ) were mated with transgenic mice carrying the Cre recombinase gene under the control of the rat nestin promoter and enhancer (Tronche et al, 1999;Ellis et al, 2003). Progeny were genotyped by PCR after blinded experiments (Ellis et al, 2003).…”

Section: Micementioning

confidence: 99%

“…Progeny were genotyped by PCR after blinded experiments (Ellis et al, 2003). Cerebella were dissected into four equal sagittal parts, paraffin-embedded, sectioned and stained with H&E. The average width of the EGL was determined by eight measurements, covering the same areas of the cerebellum for each genotype.…”

Section: Micementioning

confidence: 99%

Patched1 deletion increases N-Myc protein stability as a mechanism of medulloblastoma initiation and progression

et al. 2009

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Patched 1 conditional null allele in mice

Cited by 95 publications

References 25 publications

Suppressor of Fused Controls Mid-Hindbrain Patterning and Cerebellar Morphogenesis via GLI3 Repressor

Suppressor of Fused Controls Mid-Hindbrain Patterning and Cerebellar Morphogenesis via GLI3 Repressor

MicroRNA Biogenesis and Hedgehog-Patched Signaling Cooperate to Regulate an Important Developmental Transition in Granule Cell Development

Patched1 deletion increases N-Myc protein stability as a mechanism of medulloblastoma initiation and progression

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