Overexpression of MATH1 Disrupts the Coordination of Neural Differentiation in Cerebellum Development

Helms, Amy W.; Gowan, Katherine; Abney, Andrew L.; Savage, Trisha K.; Johnson, Jane E.

doi:10.1006/mcne.2000.0969

Cited by 65 publications

(52 citation statements)

References 62 publications

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“…Significantly, our gain-of-function transgenics reproduce the cerebellar phenotype of reduced size and foliation seen in the cyclin D1/D2 null and Math1-overexpressing mouse models (Helms et al, 2001;Ciemerych et al, 2002). However, Math1 overexpression in vivo was not associated with decreased BrdU incorporation (Helms et al, 2001), suggesting that its activity requires coordination with cell cycle arrest, which could be exerted by a G 1 checkpoint regulator such as PC3, as we show here (Fig.…”

Section: Pc3-dependent Induction Of Math1 and Cell Cycle Arrest Are Csupporting

confidence: 59%

“…Although apparently not involved in the process of specification of GCPs, Math1 is essential for their differentiation, as demonstrated by experiments of ablation in vivo and in vitro (Ben-Arie et al, 1997;Gazit et al, 2004). Consistently, its overexpression in vivo has been shown to drive the expression of early differentiation markers in postmitotic granule cells, confirming a role of Math1 in their differentiation (Helms et al, 2001). Thus, the increased differentiation of granule cells associated with the expression of PC3 can be plausibly dependent on the induction of Math1 by PC3.…”

Section: Pc3-dependent Induction Of Math1 and Cell Cycle Arrest Are Cmentioning

confidence: 64%

“…To further analyze the differentiation of GCPs at P1, we studied the expression of the basic helix-loop-helix transcription factor Math1, which is normally expressed in GCPs (Akazawa et al, 1995;Ben-Arie et al, 1997Helms et al, 2001). In both Tgs, a marked increase in Math1 expression was identified in the outer EGL (Fig.…”

Section: Math1 Expressionmentioning

confidence: 99%

“…The green line in the schematic representation of the Math1 mouse gene and of the constructs shows the promoter region analyzed). Math1 gene enhancer sequence (Helms et al, 2000) was not transcriptionally stimulated by PC3 [construct pGL3-Math1-enh (Helms et al, 2001, corresponding to their construct #9)] (see Materials and Methods) (indicated by red bars in the luciferase assays; the red boxes in the scheme below show the enhancer region analyzed). Min.…”

Section: Pc3-dependent Induction Of Math1 and Cell Cycle Arrest Are Cmentioning

confidence: 99%

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Dual Control of Neurogenesis byPC3through Cell Cycle Inhibition and Induction ofMath1

Canzoniere¹,

Farioli-Vecchioli

Conti³

et al. 2004

J. Neurosci.

101

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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 G 1 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 Math1. 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.

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Section: Pc3-dependent Induction Of Math1 and Cell Cycle Arrest Are Csupporting

confidence: 59%

Section: Pc3-dependent Induction Of Math1 and Cell Cycle Arrest Are Cmentioning

confidence: 64%

Section: Math1 Expressionmentioning

confidence: 99%

Section: Pc3-dependent Induction Of Math1 and Cell Cycle Arrest Are Cmentioning

confidence: 99%

See 2 more Smart Citations

Dual Control of Neurogenesis byPC3through Cell Cycle Inhibition and Induction ofMath1

Canzoniere¹,

Farioli-Vecchioli

Conti³

et al. 2004

J. Neurosci.

101

View full text Add to dashboard Cite

show abstract

“…Overexpression and deletion studies have shown that correct levels of Math1 are required for granule neuron differentiation making it obligatory to use an inducible system [8,22]. Using an inducible system, we were able to determine that the most appropriate window for Math1 transient expression corresponded to the EBs stage that mimics signaling centers [6].…”

Section: Discussionmentioning

confidence: 99%

Conditional Induction of Math1 Specifies Embryonic Stem Cells to Cerebellar Granule Neuron Lineage and Promotes Differentiation into Mature Granule Neurons

et al. 2013

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Directing differentiation of embryonic stem cells (ESCs) to specific neuronal subtype is critical for modeling disease pathology in vitro. An attractive means of action would be to combine regulatory differentiation factors and extrinsic inductive signals added to the culture medium. In this study, we have generated mature cerebellar granule neurons by combining a temporally controlled transient expression of Math1, a master gene in granule neuron differentiation, with inductive extrinsic factors involved in cerebellar development. Using a Tetracyclin-On transactivation system, we overexpressed Math1 at various stages of ESCs differentiation and found that the yield of progenitors was considerably increased when Math1 was induced during embryonic body stage. Math1 triggered expression of Mbh1 and Mbh2, two target genes directly involved in granule neuron precursor formation and strong expression of early cerebellar territory markers En1 and NeuroD1.Three weeks after induction, we observed a decrease in the number of glial cells and an increase in that of neurons albeit still immature. Combining Math1 induction with extrinsic factors specifically increased the number of neurons that expressed Pde1c, Zic1, and GABAa6R characteristic of mature granule neurons, formed ''T-shaped'' axons typical of granule neurons, and generated synaptic contacts and action potentials in vitro. Finally, in vivo implantation of Math1-induced progenitors into young adult mice resulted in cell migration and settling of newly generated neurons in the cerebellum. These results show that conditional induction of Math1 drives ESCs toward the cerebellar fate and indicate that acting on both intrinsic and extrinsic factors is a powerful means to modulate ESCs differentiation and maturation into a specific neuronal lineage. STEM CELLS 2013;31:652-665 Disclosure of potential conflicts of interest is found at the end of this article.

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Onset of Tlx‐3 expression in the chick cerebellar cortex correlates with the morphological development of fissures and delineates a posterior transverse boundary

Logan

Millar

Bharadia

et al. 2002

J of Comparative Neurology

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Recent studies have shown that the mammalian cerebellar cortex can be subdivided into a reproducible array of zones and stripes. In particular, discontinuous patterns of gene expression together with mutational analysis suggest that there are at least four distinct transverse zones along the rostrocaudal axis in mouse: the anterior zone (lobules I-V), the central zone (lobules VI and VII), the posterior zone (lobules VIII and IX), and the nodular zone (lobule X). Here we show that the divergent homeobox-containing transcription factor, Tlx- 3 (also known as Hox11L2 or Rnx) is transiently expressed in external granule cells in a distinct transverse domain of the developing chick cerebellar cortex. Expression is first detected at Hamburger and Hamilton (HH) stage 35. Interestingly, Tlx-3 mRNA expression is initially confined to, and coincident with, the morphological development of fissures. Slightly later, at HH stage 38, expression extends throughout the developing external granular layer (EGL) of lobules I-IXab. Notably, no Tlx-3 expression was detected in lobules IXc and X at any developmental time point examined. Expression is noticeably stronger in nonproliferating cells located in the deep layer of the EGL. Tlx-3 expression is downregulated as granule cells migrate inward to form the internal granule layer and is undetectable shortly after birth. These results suggest that Tlx-3 is expressed as granule cells become postmitotic and suggest that Tlx-3 may play a role in the differentiation of distinct neuronal populations in the cerebellum.

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Overexpression of MATH1 Disrupts the Coordination of Neural Differentiation in Cerebellum Development

Cited by 65 publications

References 62 publications

Dual Control of Neurogenesis byPC3through Cell Cycle Inhibition and Induction ofMath1

Dual Control of Neurogenesis byPC3through Cell Cycle Inhibition and Induction ofMath1

Conditional Induction of Math1 Specifies Embryonic Stem Cells to Cerebellar Granule Neuron Lineage and Promotes Differentiation into Mature Granule Neurons

Onset of Tlx‐3 expression in the chick cerebellar cortex correlates with the morphological development of fissures and delineates a posterior transverse boundary

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