Transposon mutagenesis with coat color genotyping identifies an essential role for Skor2 in sonic hedgehog signaling and cerebellum development

Abstract

SUMMARYCorrect development of the cerebellum requires coordinated sonic hedgehog (Shh) signaling from Purkinje to granule cells. How Shh expression is regulated in Purkinje cells is poorly understood. Using a novel tyrosinase minigene-tagged Sleeping Beauty transposon-mediated mutagenesis, which allows for coat color-based genotyping, we created mice in which the Ski/Sno family transcriptional co-repressor 2 (Skor2) gene is deleted. Loss of Skor2 leads to defective Purkinje cell development, a severe reduction of granule cell proliferation and a malformed cerebellum. Skor2 is specifically expressed in Purkinje cells in the brain, where it is required for proper expression of Shh. Skor2 overexpression suppresses BMP signaling in an HDAC-dependent manner and stimulates Shh promoter activity, suggesting that Skor2 represses BMP signaling to activate Shh expression. Our study identifies an essential function for Skor2 as a novel transcriptional regulator in Purkinje cells that acts upstream of Shh during cerebellum development.

DrosophilaCORL is required for Smad2-mediated activation of Ecdysone Receptor expression in the mushroom body

“…This hypothesis is supported by a recent paper describing a loss-of-function phenotype for mouse Corl2 in mice (Wang et al, 2011). In addition to gross cerebellar defects, homozygous mouse Corl2 mutant mice lack sonic hedgehog expression in Purkinje cells.…”

Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines

“…Initially, the involvement of Shh signaling in embryonic development of mammal species was discovered. Deprivation of certain molecules of this pathway was found to cause cerebellum atrophy and limb defects in rats (27)(28)(29)(30). Since neoplasms and embryonic development share similar molecular signaling processes, numerous studies have examined and demonstrated the core role of Shh signaling in maintaining tumor growth and cancer cell survival (12).…”

Mice lacking the transcription factor SHOX2 display impaired cerebellar development and deficits in motor coordination

“…Ultimately, it appears that Shox2 is required to maintain proper Shh expression levels in the developing postnatal cerebellum; whether this occurs via direct or indirect regulation of Shh and whether loss of normal SHH levels or loss of SHOX2 directly is responsible for the premature onset of Bmp4 expression has yet to be determined. Since this phenotypic effect is most prominent in the dorsal vermis, factors other than SHOX2 must contribute to Shh regulation in other regions of the cerebellum, such as RORα, SKOR2 or other spatially restricted Purkinje cell specific genes (Gold et al, 2003;Otero et al, 2014;Wang et al, 2011).…”

“…Disruption of the balance between these signals can result in medulloblastoma due to the constant activation of the SHH signal and resulting uncontrolled GCP proliferation (Grimmer and Weiss, 2008;Zhao et al, 2008). Despite the pivotal function of SHH in cerebellar development, the upstream regulators that establish and/or maintain the Shh expression pattern in this brain region are only just starting to be uncovered (Gold et al, 2003;Wang et al, 2011;Xenaki et al, 2011). In addition, while a number of studies have demonstrated that BMP signaling can antagonize SHH-mediated GCP proliferation (Grimmer and Weiss, 2008;Rios et al, 2004), the signals responsible for the correct timing and proper balance of cerebellar GCP proliferation and granule cell differentiation have yet to be elucidated.…”