Cerebellum morphogenesis: the foliation pattern is orchestrated by multi-cellular anchoring centers.
BACKGROUND
The cerebellum has a striking morphology consisting of folia separated by fissures of different lengths. Since folia in mammals likely serve as a broad platform on which the anterior-posterior organization of the sensory-motor circuits of the cerebellum are built, it is important to understand how such complex morphology arises.


RESULTS
Using a combination of genetic inducible fate mapping, high-resolution cellular analysis and mutant studies in mouse, we demonstrate that a key event in initiation of foliation is the acquisition of a distinct cytoarchitecture in the regions that will become the base of each fissure. We term these regions 'anchoring centers'. We show that the first manifestation of anchoring centers when the cerebellar outer surface is smooth is an increase in proliferation and inward thickening of the granule cell precursors, which likely causes an associated slight invagination of the Purkinje cell layer. Thereafter, granule cell precursors within anchoring centers become distinctly elongated along the axis of the forming fissure. As the outer cerebellar surface begins to fold inwards, Bergmann glial fibers radiate in towards the base of the immature fissure in a fan shape. Once the anchoring center is formed, outgrowth of folia seems to proceed in a self-sustaining manner driven by granule cell migration along Bergmann glial fibers. Finally, by analyzing a cerebellum foliation mutant (Engrailed 2), we demonstrate that changing the timing of anchoring center formation leads to predictable changes in the shape and size of the surrounding folia.


CONCLUSIONS
We present a new cellular model of the initial formation of cerebellar fissures with granule cells providing the driving physical force. Both the precise timing of the appearance of anchoring centers at the prospective base of each fissure and the subsequent coordinated action of granule cells and Bergmann glial fibers within the anchoring centers dictates the shape of the folia.
Developmental Biology Program, Sloan-Kettering Institute, York Avenue, New York, NY 10021, USA. sudarova@mskcc.org
Anamaria
A
Sudarov
Alexandra L
AL
Joyner
D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002525:Cerebellar Cortex / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008940:Mitotic Index; D008959:Models, Neurological; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D000099266:Engrailed 2 Protein
D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000099266:Engrailed 2 Protein