Dual Control of Neurogenesis byPC3through Cell Cycle Inhibition and Induction ofMath1

Abstract

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.

Btg1 and Btg2 gene expression during early chick development

“…Experiments in vitro and in vivo using different animal species have shown that Btg2 is expressed in differentiating neural precursors that switch from proliferative to neurongenerating division (Iacopetti et al, 1994(Iacopetti et al, , 1999, and that Btg2 overexpression results in negative regulation of the cell cycle and induction of neuronal differentiation (Malatesta et al, 2000;Corrente et al, 2002;elGhissassi et al, 2002;Canzoniere et al, 2004). Our results about Btg2 expression in the neural tube are consistent with those reported in mice.…”

“…Our results about Btg2 expression in the neural tube are consistent with those reported in mice. Interestingly, in vivo overexpression of Btg2 in mouse neuroepithelial cells affected cerebellar development by a mechanism that involves a double action of Btg2: (1) down-regulation of cyclin D1 promoting cell cycle exit, and (2) stimulation of Math1 promoter activity, stimulating differentiation of cerebellar progenitors located in the hindbrain rhombic lip (Canzoniere et al, 2004). Our results in the chick show that Btg2 is also highly expressed in the rhombic lip area, suggesting again a conserved function.…”

“…It has been suggested that Btg proteins exert cellular functions by interacting with transcriptional coactivators or corepressors, hence modulating their transcriptional activities (Matsuda et al, 2001;Tirone, 2001;Duriez et al, 2004;Lim, 2006). For example, it has been found that Btg2 impairs G1-S cell cyclephase progression by inhibiting cyclin D1 transcription (Guardavaccaro et al, 2000), that it can associate with HoxB9 (Prevot et al, 2000), and BMPregulated Smad1 and 8 (Park et al, 2004) to promote their transcriptional activity, and that it can enhance Math1 promoter activity (Canzoniere et al, 2004). Similarly, Btg1 has been shown to interact with and stimulate the activity of transcription factors that positively regulate myogenic processes, in particular myogenic factors such as MyoD, all-trans retinoic acid receptors, and the T3 receptor TR␣1 (Busson et al, 2005).…”

“…Btg1 has been shown to modulate avian myoblast differentiation in vitro (Marchal et al, 1995;Rodier et al, 1999), and Btg2 can promote differentiation and survival of cultured-neural cells (Corrente et al, 2002;el-Ghissassi et al, 2002). Overexpression of Btg2 during mouse embryonic development in vivo regulates cell cycle exit and differentiation of mouse cerebellar progenitors (Canzoniere et al, 2004). Furthermore, Btg2 is expressed at the onset of neurogenesis in neuroepithelial cells, concomitantly with the switch from proliferative to neurogenic divisions (Iacopetti et al, 1994(Iacopetti et al, , 1999Hammerle et al, 2002).…”

“…Information about developmental expression of Btg genes is still fragmentary and limited to individual genes in specific developmental processes in amphioxus, xenopus, zebrafish, and mouse (Iacopetti et al, 1994(Iacopetti et al, , 1999Holland et al, 1997;Buanne et al, 2000;Chen et al, 2000;Saka et al, 2000;Sakaguchi et al, 2001;Thisse et al, 2001;Hammerle et al, 2002;Canzoniere et al, 2004;Park et al, 2004;Thisse and Thisse, 2004;Sugimoto et al, 2005Sugimoto et al, , 2007Wessely et al, 2005;Feng et al, 2007), and there is no detailed description of the expression pattern of any member of the family in the chick embryo. To gain insights on the function of these genes during development, and since Btg1 and Btg2 are the more closely related genes in the family, we sought to analyse and compare their expression profile during early stages of chick development.…”