Neurogenin 2 regulates progenitor cell-cycle progression and Purkinje cell dendritogenesis in cerebellar development.
By serving as the sole output of the cerebellar cortex, integrating a myriad of afferent stimuli, Purkinje cells (PCs) constitute the principal neuron in cerebellar circuits. Several neurodegenerative cerebellar ataxias feature a selective cell-autonomous loss of PCs, warranting the development of regenerative strategies. To date, very little is known as to the regulatory cascades controlling PC development. During central nervous system development, the proneural gene neurogenin 2 (Neurog2) contributes to many distinct neuronal types by specifying their fate and/or dictating development of their morphological features. By analyzing a mouse knock-in line expressing Cre recombinase under the control of Neurog2 cis-acting sequences we show that, in the cerebellar primordium, Neurog2 is expressed by cycling progenitors cell-autonomously fated to become PCs, even when transplanted heterochronically. During cerebellar development, Neurog2 is expressed in G1 phase by progenitors poised to exit the cell cycle. We demonstrate that, in the absence of Neurog2, both cell-cycle progression and neuronal output are significantly affected, leading to an overall reduction of the mature cerebellar volume. Although PC fate identity is correctly specified, the maturation of their dendritic arbor is severely affected in the absence of Neurog2, as null PCs develop stunted and poorly branched dendrites, a defect evident from the early stages of dendritogenesis. Thus, Neurog2 represents a key regulator of PC development and maturation.
Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy.
Marta
M
Florio
Ketty
K
Leto
Luca
L
Muzio
Andrea
A
Tinterri
Aurora
A
Badaloni
Laura
L
Croci
Paola
P
Zordan
Valeria
V
Barili
Ilaria
I
Albieri
François
F
Guillemot
Ferdinando
F
Rossi
G Giacomo
GG
Consalez
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle; D019070:Cell Lineage; D002531:Cerebellum / Q000254:growth & development* / Q000502:physiology; D003712:Dendrites / Q000502:physiology*; D005260:Female; D055879:Gene Knock-In Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology; D011247:Pregnancy; D011689:Purkinje Cells / Q000502:physiology*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000502:physiology
D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C102938:Neurog2 protein, mouse