Ikaros-1 couples cell cycle arrest of late striatal precursors with neurogenesis of enkephalinergic neurons.
During central nervous system development, several transcription factors regulate the differentiation of progenitor cells to postmitotic neurons. Here we describe a novel role for Ikaros-1 in the generation of late-born striatal neurons. Our results show that Ikaros-1 is expressed in the boundary of the striatal germinal zone (GZ)/mantle zone (MZ), where it induces cell cycle arrest of neural progenitors by up-regulation of the cyclin-dependent kinase inhibitor (CDKi) p21(Cip1/Waf1). This effect is coupled with the neuronal differentiation of late precursors, which in turn is critical for the second wave of striatal neurogenesis that gives rise to matrix neurons. Consistently, Ikaros(-/-) mice had fewer striatal projecting neurons and, in particular, enkephalin (ENK)-positive neurons. In addition, overexpression of Ikaros-1 in primary striatal cultures increases the number of calbindin- and ENK-positive neurons. Our results also show that Ikaros-1 acts downstream of the Dlx family of transcription factors, insofar as its expression is lost in Dlx1/2 double knockout mice. However, we demonstrate that Ikaros-1 and Ebf-1 independently regulate the final determination of the two populations of striatal projection neurons of the matrix compartment, ENK- and substance P-positive neurons. In conclusion, our findings identify Ikaros-1 as a modulator of cell cycle exit of neural progenitors that gives rise to the neurogenesis of ENK-positive striatal neurons.
Martín-Ibáñez
Raquel
R
Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
Crespo
Empar
E
Urbán
Noelia
N
Sergent-Tanguy
Solène
S
Herranz
Cristina
C
Jaumot
Montserrat
M
Valiente
Manuel
M
Long
Jason E
JE
Pineda
José Ramón
JR
Andreu
Celia
C
Rubenstein
John L R
JL
Marín
Oscar
O
Georgopoulos
Katia
K
Mengod
Guadalupe
G
Fariñas
Isabel
I
Bachs
Oriol
O
Alberch
Jordi
J
Canals
Josep M
JM
D000818:Animals; D064026:Calbindins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology / Q000196:embryology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004525:Efferent Pathways / Q000166:cytology / Q000196:embryology; D004745:Enkephalins / Q000378:metabolism*; D018816:Genes, cdc / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
D064026:Calbindins; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C088334:Distal-less homeobox proteins; C489921:Ebf1 protein, mouse; D004745:Enkephalins; D018398:Homeodomain Proteins; D064030:S100 Calcium Binding Protein G; D015534:Trans-Activators; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D013373:Substance P