Astroglial cells in the external granular layer are precursors of cerebellar granule neurons in neonates.
It is well established that cerebellar granule cell precursors (GCPs) initially derive from progenitors in the rhombic lip of the embryonic cerebellar primordium. GCPs proliferate and migrate tangentially across the cerebellum to form the external granule cell layer (EGL) in late embryogenesis and early postnatal development. It is unclear whether GCPs are specified exclusively in the embryonic rhombic lip or whether their precursor persists in the neonate. Using transgenic mice expressing DsRed under the human glial fibrillary acidic protein (hGFAP) promoter, we found 2 populations of DsRed(+) cells in the EGL in the first postnatal week defined by bright and faint DsRed-fluorescent signal. Bright DsRed(+) cells have a protein expression profile and electrophysiological characteristics typical of astrocytes, but faint DsRed(+) cells in the EGL and internal granule cell layer (IGL) express markers and physiological properties of immature neurons. To determine if these astroglial cells gave rise to GCPs, we genetically tagged them with EGFP or betagal reporter genes at postnatal day (P)3-P5 using a hGFAP promoter driven inducible Cre recombinase. We found that GFAP promoter(+) cells in the EGL are proliferative and express glial and neural stem cell markers. In addition, immature granule cells (GCs) en route to the IGL at P12 as well as GCs in the mature cerebellum, 30days after recombination, express the reporter protein, suggesting that GFAP promoter(+) cells in the EGL generate a subset of granule cells. The identification of glial cells which function as neuronal progenitor cells profoundly impacts our understanding of cellular plasticity in the developing cerebellum.
Silbereis
John
J
Child Study Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Heintz
Tristan
T
Taylor
Mary Morgan
MM
Ganat
Yosif
Y
Ment
Laura R
LR
Bordey
Angelique
A
Vaccarino
Flora
F
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000276:immunology; D019070:Cell Lineage / Q000502:physiology; D002531:Cerebellum / Q000166:cytology*; D017930:Genes, Reporter; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000166:cytology; D011401:Promoter Regions, Genetic / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors; D001616:beta-Galactosidase
D051792:Basic Helix-Loop-Helix Proteins; D005904:Glial Fibrillary Acidic Protein; D049452:Green Fluorescent Proteins; D019426:Integrases; D001616:beta-Galactosidase; C500943:Atoh1 protein, mouse; C485184:enhanced green fluorescent protein; C045073:Cre recombinase
Dev Neurosci. 2004 Mar-Aug;26(2-4):148-65
15711057
Trends Neurosci. 2005 May;28(5):219-21
15866195
Nature. 1997 Nov 13;390(6656):169-72
9367153
Development. 2000 Jun;127(11):2367-82
10804179
Development. 1999 Oct;126(20):4395-404
10498676
J Neurosci. 2001 Jan 1;21(1):159-68
11150332
Brain Res. 1984 Aug;317(2):201-9
6383523
J Physiol. 2004 Nov 1;560(Pt 3):721-36
15331688
Neuron. 2003 Mar 6;37(5):751-64
12628166
J Neurosci. 2004 Mar 3;24(9):2202-11
14999071
Dev Neurosci. 2000;22(1-2):139-53
10657706
J Neurosci. 2001 Jan 15;21(2):527-40
11160432
Development. 2005 Oct;132(20):4497-508
16162650
Glia. 1998 Jul;23(3):191-9
9633804
Neuron. 1996 Sep;17(3):389-99
8816703
Dev Biol. 2008 May 1;317(1):246-59
18353302
Stem Cells. 2009 May;27(5):1152-63
19418461
Annu Rev Neurosci. 1995;18:385-408
7605067
Cancer Cell. 2008 Aug 12;14(2):123-34
18691547
Neuron. 2005 Oct 6;48(1):17-24
16202705
Mol Cell Neurosci. 2006 Apr;31(4):676-84
16458536
Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11619-24
10500226
Development. 2000 Dec;127(24):5253-63
11076748
Circ Res. 2006 Jun 23;98(12):1547-54
16709902
Dev Biol. 2006 Jul 1;295(1):52-66
16631155
Nat Neurosci. 2004 Nov;7(11):1233-41
15494728
Brain Res. 2006 Jul 12;1099(1):8-17
16797497
J Neurosci. 2006 Aug 16;26(33):8609-21
16914687
Nat Rev Neurosci. 2001 Jul;2(7):484-91
11433373
Development. 1990 Jan;108(1):19-31
2351063
J Neurosci. 1994 Mar;14(3 Pt 1):1030-7
8120611
Altern Lab Anim. 2007 Mar;35(1):61-70
17411353
Nat Neurosci. 2005 Jun;8(6):723-9
15908947
Nat Genet. 1999 Jan;21(1):70-1
9916792
Glia. 2006 Feb;53(3):277-93
16267834
J Neurosci. 2001 Sep 15;21(18):7153-60
11549726
Neuroscience. 2002;112(4):977-91
12088755
Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1211-6
14745007
J Neurosci. 2002 Jan 1;22(1):218-25
11756505