Differential timing of granule cell production during cerebellum development underlies generation of the foliation pattern.
The mouse cerebellum (Cb) has a remarkably complex foliated three-dimensional (3D) structure, but a stereotypical cytoarchitecture and local circuitry. Little is known of the cellular behaviors and genes that function during development to determine the foliation pattern. In the anteroposterior axis the mammalian cerebellum is divided by lobules with distinct sizes, and the foliation pattern differs along the mediolateral axis defining a medial vermis and two lateral hemispheres. In the vermis, lobules are further grouped into four anteroposterior zones (anterior, central, posterior and nodular zones) based on genetic criteria, and each has distinct lobules. Since each cerebellar afferent group projects to particular lobules and zones, it is critical to understand how the 3D structure of the Cb is acquired. During cerebellar development, the production of granule cells (gcs), the most numerous cell type in the brain, is required for foliation. We hypothesized that the timing of gc accumulation is different in the four vermal zones during development and contributes to the distinct lobule morphologies.



In order to test this idea, we used genetic inducible fate mapping to quantify accumulation of gcs in each lobule during the first two postnatal weeks in mice. The timing of gc production was found to be particular to each lobule, and delayed in the central zone lobules relative to the other zones. Quantification of gc proliferation and differentiation at three time-points in lobules representing different zones, revealed the delay involves a later onset of maximum differentiation and prolonged proliferation of gc progenitors in the central zone. Similar experiments in Engrailed mutants (En1 (-/+) ;En2 (-/-) ), which have a smaller Cb and altered foliation pattern preferentially outside the central zone, showed that gc production, proliferation and differentiation are altered such that the differences between zones are attenuated compared to wild-type mice.



Our results reveal that gc production is differentially regulated in each zone of the cerebellar vermis, and our mutant analysis indicates that the dynamics of gc production plays a role in determining the 3D structure of the Cb.
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.|Present Address: Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
Emilie
E
Legué
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Jackie L
JL
Gottshall
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Edouard
E
Jaumouillé
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Alberto
A
Roselló-Díez
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.|Neuroscience Program of Weill Cornell Graduate School of Medical Sciences, New York, USA.
Wei
W
Shi
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Luis Humberto
LH
Barraza
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Senna
S
Washington
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Rachel L
RL
Grant
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. joynera@mskcc.org.|Neuroscience Program of Weill Cornell Graduate School of Medical Sciences, New York, USA. joynera@mskcc.org.|Biochemistry, Cell and Molecular Biology Program of Weill Cornell Graduate School of Medical Sciences, New York, USA. joynera@mskcc.org.
Alexandra L
AL
Joyner
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002531:Cerebellum / Q000254:growth & development*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D000099266:Engrailed 2 Protein
D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000099266:Engrailed 2 Protein; C080330:En1 protein, mouse
Differentiation; En2; Engrailed genes; Lobules; Proliferation; gcps