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A failure in the control of proliferation of cerebellar granule neuron precursor cells (GCPs), located in the external granular layer (EGL) of the cerebellum, gives rise to medulloblastoma. To investigate the process of neoplastic transformation of GCPs, we generated a new medulloblastoma model by crossing Patchedl heterozygous mice, which develop medulloblastomas with low frequency, with mice lacking the Tis21 gene. Overexpression of Tis21 is known to inhibit proliferation and trigger differentiation of GCPs; its expression decreases in human medulloblastomas. Double-knock-out mice show a striking increase in the frequency of medulloblastomas and hyperplastic EGL lesions, formed by preneoplastic GCPs. Tis21 deletion does not affect the proliferation of GCPs but inhibits their differentiation and, chiefly, their intrinsic ability to migrate outside the EGL. This defect of migration may represent an important step in medulloblastoma formation, as GCPs, remaining longer in the EGL proliferative niche, may become more prone to transformation. By genome-wide analysis, we identified the chemokine Cxcl3 as a target of Tis21. Cxcl3 is downregulated in Ti's2i-null GCPs of EGL and lesions; addition of Cxcl3 to cerebellar slices rescues the defective migration of T/s2/-null GCPs and, remarkably, reduces the area of hyperplastic lesions. As Tis21 activates Cxcl3 transcription, our results suggest that Tis21 induces migration of GCPs through Cxcl3, which may represent a novel target for medulloblastoma therapy. [ABSTRACT FROM AUTHOR]

Dopamine D2 receptor (D2DR)-mediated transmission in the striatum is remarkably flexible, and changes in its efficacy have been heavily implicated in a variety of physiological and pathological conditions. Although receptor-associated proteins are clearly involved in specific forms of synaptic plasticity, the molecular mechanisms regulating the sensitivity of D2 receptors in this brain area are essentially obscure. We have studied the physiological responses of the D2DR stimulations in mice lacking the brain cytoplasmicRNABC1, a small noncoding dendritically localized RNA that is supposed to play a role in mRNA translation. We show that the efficiency of D2-mediated transmission regulating striatal GABA synapses is under the control of BC1 RNA, through a negative influence onD2 receptor protein level affecting the functional pool of receptors. Ablation of the BC1 gene did not result in widespread dysregulation of synaptic transmission, because the sensitivity of cannabinoid CB1 receptors was intact in the striatum of BC1 knock-out (KO) mice despite D2 and CB1 receptors mediated similar electrophysiological actions. Interestingly, the fragileXmental retardation protein FMRP, one of the multiple BC1 partners, is not involved in the BC1 effects on the D2-mediated transmission. Because D2DR mRNA is apparently equally translated in the BC1-KO and wild-type mice, whereas the protein level is higher in BC1-KO mice, we suggest that BC1 RNA controls D2DR indirectly, probably regulating translation of molecules involved in D2DR turnover and/or stability. [ABSTRACT FROM AUTHOR]

Growing evidence indicates that cell cycle arrest and neurogenesis are highly coordinated and interactive processes, governed by cell cycle genes and neural transcription factors. The gene PC3 (Tis21/BTG2) is expressed in the neuroblast throughout the neural tube and inhibits cell cycle progression at the G1 checkpoint by repressing cyclin D1 transcription. We generated inducible mouse models in which the expression of PC3 was upregulated in neuronal precursors of the neural tube and of the cerebellum. These mice exhibited a marked increase in the production of postmitotic neurons and impairment of cerebellar development. Cerebellar granule precursors of PC3 transgenic mice displayed inhibition of cyclin D1 expression and a strong increase in the expression of Math1, a transcription factor required for their differentiation. Furthermore, PC3, encoded by a recombinant adenovirus, also induced Math1 in postmitotic granule cells in vitro and stimulated the Math1 promoter activity. In contrast, PC3 expression was unaffected in the cerebellar primordium of Math1 null mice, suggesting that PC3 acts upstream to Mattel. As a whole, our data suggest that cell cycle exit of cerebellar granule cell precursors and the onset of cerebellar neurogenesis are coordinated by PC3 through transcriptional control of cyclin D1 and Math1, respectively. [ABSTRACT FROM AUTHOR]

A failure in the control of proliferation of cerebellar granule neuron precursor cells (GCPs), located in the external granular layer (EGL) of the cerebellum, gives rise to medulloblastoma. To investigate the process of neoplastic transformation of GCPs, we generated a new medulloblastoma model by crossing Patched1 heterozygous mice, which develop medulloblastomas with low frequency, with mice lacking the Tis21 gene. Overexpression of Tis21 is known to inhibit proliferation and trigger differentiation of GCPs; its expression decreases in human medulloblastomas. Double-knock-out mice show a striking increase in the frequency of medulloblastomas and hyperplastic EGL lesions, formed by preneoplastic GCPs. Tis21 deletion does not affect the proliferation of GCPs but inhibits their differentiation and, chiefly, their intrinsic ability to migrate outside the EGL. This defect of migration may represent an important step in medulloblastoma formation, as GCPs, remaining longer in the EGL proliferative niche, may become more prone to transformation. By genome-wide analysis, we identified the chemokine Cxcl3 as a target of Tis21. Cxcl3 is downregulated in Tis21-null GCPs of EGL and lesions; addition of Cxcl3 to cerebellar slices rescues the defective migration of Tis21-null GCPs and, remarkably, reduces the area of hyperplastic lesions. As Tis21 activates Cxcl3 transcription, our results suggest that Tis21 induces migration of GCPs through Cxcl3, which may represent a novel target for medulloblastoma therapy.

Dopamine D(2) receptor (D(2)DR)-mediated transmission in the striatum is remarkably flexible, and changes in its efficacy have been heavily implicated in a variety of physiological and pathological conditions. Although receptor-associated proteins are clearly involved in specific forms of synaptic plasticity, the molecular mechanisms regulating the sensitivity of D(2) receptors in this brain area are essentially obscure. We have studied the physiological responses of the D(2)DR stimulations in mice lacking the brain cytoplasmic RNA BC1, a small noncoding dendritically localized RNA that is supposed to play a role in mRNA translation. We show that the efficiency of D(2)-mediated transmission regulating striatal GABA synapses is under the control of BC1 RNA, through a negative influence on D(2) receptor protein level affecting the functional pool of receptors. Ablation of the BC1 gene did not result in widespread dysregulation of synaptic transmission, because the sensitivity of cannabinoid CB(1) receptors was intact in the striatum of BC1 knock-out (KO) mice despite D(2) and CB(1) receptors mediated similar electrophysiological actions. Interestingly, the fragile X mental retardation protein FMRP, one of the multiple BC1 partners, is not involved in the BC1 effects on the D(2)-mediated transmission. Because D(2)DR mRNA is apparently equally translated in the BC1-KO and wild-type mice, whereas the protein level is higher in BC1-KO mice, we suggest that BC1 RNA controls D(2)DR indirectly, probably regulating translation of molecules involved in D(2)DR turnover and/or stability.