|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
First published online February 2, 2004
doi: 10.1242/10.1242/dev.00982
1 Cell and Animal Biology, The Institute of Life Sciences, The Hebrew University
of Jerusalem, Jerusalem 91904, Israel
2 Roland Center for Neurodegenerative Diseases, The Institute of Life Sciences,
The Hebrew University of Jerusalem, Jerusalem 91904, Israel
Author for correspondence (e-mail:
nbenarie{at}vms.huji.ac.il)
Accepted 12 November 2003
Cerebellar granule cells (CGC) are the most abundant neurons in the mammalian brain, and an important tool for unraveling molecular mechanisms underlying neurogenesis. Math1 is a bHLH transcription activator that is essential for the genesis of CGC. To delineate the effects of Math1 on CGC differentiation, we generated and studied primary cultures of CGC progenitors from Math1/lacZ knockout mice. Rhombic lip precursors appeared properly positioned, expressed CGC-specific markers, and maintained Math1 promoter activity in vivo and in vitro, suggesting that Math1 is not essential for the initial stages of specification or survival of CGC. Moreover, the continuous activity of Math1 promoter in the absence of MATH1, indicated that MATH1 was not necessary for the activation of its own expression. After 6, but not 3, days in culture, Math1 promoter activity was downregulated in control cultures, but not in cells from Math1 null mice, thus implying that Math1 participates in a negative regulatory feedback loop that is dependent on increased levels of MATH1 generated through the positive autoregulatory feedback loop. In addition, Math1 null CGC did not differentiate properly in culture, and were unable to extend processes. All Notch signaling pathway receptors and ligands tested were expressed in the rhombic lip at embryonic date 14, with highest levels of Notch2 and Jag1. However, Math1-null rhombic lip cells presented conspicuous downregulation of Notch4 and Dll1. Moreover, of the two transcriptional repressors known to antagonize Math1, Hes5 (but not Hes1) was downregulated in Math1-null rhombic lip tissue and primary cultures, and was shown to bind MATH1, thus revealing a negative regulatory feedback loop. Taken together, our data demonstrate that CGC differentiation, but not specification, depends on Math1, which acts by regulating the level of multiple components of the Notch signaling pathway.
Key words: Rhombic lip, Cerebellum, Cerebellar granule cells, Neurite, Notch, Delta, Jagged, Hes, Knockout, Mouse
This article has been cited by other articles:
|
|
 |
|
  M. R. Grimmer and W. A. Weiss BMPs oppose Math1 in cerebellar development and in medulloblastoma Genes & Dev., March 15, 2008; 22(6): 693 - 699. [Full Text] [PDF]
|
|
|
|
|
|
H. Zhao, O. Ayrault, F. Zindy, J.-H. Kim, and M. F. Roussel Post-transcriptional down-regulation of Atoh1/Math1 by bone morphogenic proteins suppresses medulloblastoma development Genes & Dev., March 15, 2008; 22(6): 722 - 727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Briggs, I. M. Corcoran-Schwartz, W. Zhang, T. Harcke, W. L. Devereux, S. B. Baylin, C. G. Eberhart, and D. N. Watkins Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma Genes & Dev., March 15, 2008; 22(6): 770 - 785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhao, K.-M. Kwan, C. M. Mailloux, W.-K. Lee, A. Grinberg, W. Wurst, R. R. Behringer, and H. Westphal LIM-homeodomain proteins Lhx1 and Lhx5, and their cofactor Ldb1, control Purkinje cell differentiation in the developing cerebellum PNAS, August 7, 2007; 104(32): 13182 - 13186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Farioli-Vecchioli, M. Tanori, L. Micheli, M. Mancuso, L. Leonardi, A. Saran, M. T. Ciotti, E. Ferretti, A. Gulino, S. Pazzaglia, et al. Inhibition of medulloblastoma tumorigenesis by the antiproliferative and pro-differentiative gene PC3 FASEB J, July 1, 2007; 21(9): 2215 - 2225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Wang, D. Mullikin-Kilpatrick, J. E. Crandall, R. M. Gronostajski, E. D. Litwack, and D. L. Kilpatrick Nuclear Factor I Coordinates Multiple Phases of Cerebellar Granule Cell Development via Regulation of Cell Adhesion Molecules J. Neurosci., June 6, 2007; 27(23): 6115 - 6127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Pascual, I. Abasolo, A. Mingorance-Le Meur, A. Martinez, J. A. Del Rio, C. V. E. Wright, F. X. Real, and E. Soriano Cerebellar GABAergic progenitors adopt an external granule cell-like phenotype in the absence of Ptf1a transcription factor expression PNAS, March 20, 2007; 104(12): 5193 - 5198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Dvash, N. Sharon, O. Yanuka, and N. Benvenisty Molecular Analysis of LEFTY-Expressing Cells in Early Human Embryoid Bodies Stem Cells, February 1, 2007; 25(2): 465 - 472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Qin, L. Wine-Lee, K. J. Ahn, and E. B. Crenshaw III Genetic Analyses Demonstrate That Bone Morphogenetic Protein Signaling Is Required for Embryonic Cerebellar Development J. Neurosci., February 15, 2006; 26(7): 1896 - 1905. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Hutcheson, M. I. Hanson, K. B. Moore, T. T. Le, N. L. Brown, and M. L. Vetter bHLH-dependent and -independent modes of Ath5 gene regulation during retinal development Development, February 15, 2005; 132(4): 829 - 839. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Dauphinot, R. Lyle, I. Rivals, M. T. Dang, R.X. Moldrich, G. Golfier, L. Ettwiller, K. Toyama, J. Rossier, L. Personnaz, et al. The cerebellar transcriptome during postnatal development of the Ts1Cje mouse, a segmental trisomy model for Down syndrome Hum. Mol. Genet., February 1, 2005; 14(3): 373 - 384. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Hawkins and M. Lovett The developmental genetics of auditory hair cells Hum. Mol. Genet., October 1, 2004; 13(suppl_2): R289 - R296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Canzoniere, S. Farioli-Vecchioli, F. Conti, M. T. Ciotti, A. M. Tata, G. Augusti-Tocco, E. Mattei, M. K. Lakshmana, V. Krizhanovsky, S. A. Reeves, et al. Dual Control of Neurogenesis by PC3 through Cell Cycle Inhibition and Induction of Math1 J. Neurosci., March 31, 2004; 24(13): 3355 - 3369. [Abstract] [Full Text] [PDF]
|
|
