The level of sonic hedgehog signaling regulates the complexity of cerebellar foliation.
Foliation of the mouse cerebellum occurs primarily during the first 2 weeks after birth and is accompanied by tremendous proliferation of granule cell precursors (GCPs). We have previously shown that sonic hedgehog (Shh) signaling correlates spatially and temporally with fissure formation, and that Gli2 is the main activator driving Shh induced proliferation of embryonic GCPs. Here, we have tested whether the level of Shh signaling regulates the extent of cerebellar foliation. By progressively lowering signaling by removing Gli1 and Gli2 or the Shh receptor smoothened, we found the extent of foliation is gradually reduced, and that this correlates with a decrease in the duration of GCP proliferation. Importantly, the pattern of the remaining fissures in the mutants corresponds to the first fissures that form during normal development. In a complementary manner, an increase in the level and length of Shh signaling results in formation of an extra fissure in a position conserved in rat. The complexity of cerebellar foliation varies greatly between vertebrate species. Our studies have uncovered a mechanism by which the level and length of Shh signaling could be integral to determining the distinct number of fissures in each species.
Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, 540 First Avenue New York, NY 10016, USA.
JoMichelle D
JD
Corrales
Sandra
S
Blaess
Eamonn M
EM
Mahoney
Alexandra L
AL
Joyner
D000483:Alleles; D000818:Animals; D002531:Cerebellum / Q000002:abnormalities / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D006579:Heterozygote; D007150:Immunohistochemistry; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
C498520:Gli1 protein, mouse; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C465570:Shh protein, mouse; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2