Engrailed homeobox genes regulate establishment of the cerebellar afferent circuit map.
The spatial organization of the cerebellar afferent map has remarkable correspondence to two aspects of intrinsic patterning within the cerebellum embodied by a series of lobules and Purkinje cell (PC)-striped gene expression. Using male and female mice, we tested whether the Engrailed (En) homeobox genes are a common genetic substrate regulating all three systems, since they are expressed in spatially restricted domains within the cerebellum and are critical for patterning PC gene expression and foliation. Indeed, we discovered that En1/2 are necessary for the precise targeting of mossy fibers to distinct lobules, as well as their subsequent resolution into discrete parasagittal bands. Moreover, each En gene coordinately regulates afferent targeting and the striped pattern of PC protein expression (e.g., ZebrinII/AldolaseC) independent of regulating foliation. We further found that En1/2, rather than the presence of a full complement of lobules, are critical for generating PC protein stripes and mossy fiber bands, and that PC striped gene expression is determined before afferent banding. Thus, the En transcription factors not only regulate cerebellum circuit topography, but they also link afferent and efferent neurons precisely enough that alterations in PC protein expression can be used as a read out for underlying defects in circuitry. In summary, our data suggest that En1/2 are master regulators of three-dimensional organization of the cerebellum and coordinately regulate morphology, patterned gene expression, and afferent topography.
Sillitoe
Roy V
RV
Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10021, USA. roy.sillitoe@einstein.yu.edu
Vogel
Michael W
MW
Joyner
Alexandra L
AL
D000818:Animals; D001369:Axons / Q000378:metabolism; D001931:Brain Mapping; D002525:Cerebellar Cortex / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism; D009412:Nerve Fibers / Q000378:metabolism*; D009415:Nerve Net / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018998:Wheat Germ Agglutinin-Horseradish Peroxidase Conjugate / Q000378:metabolism; D000075746:Zinc Finger Protein Gli2
C080330:En1 protein, mouse; C000618551:Gli2 protein, mouse; D006360:Heat-Shock Proteins; D018398:Homeodomain Proteins; C486113:Hsbp1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D018998:Wheat Germ Agglutinin-Horseradish Peroxidase Conjugate; D000075746:Zinc Finger Protein Gli2; C106185:engrailed homeobox proteins; C071871:zebrin II