title: Ascl1 genetics reveals insights into cerebellum local circuit assembly.
abstract: Two recently generated targeted mouse alleles of the neurogenic gene Ascl1 were used to characterize cerebellum circuit formation. First, genetic inducible fate mapping (GIFM) with an Ascl1(CreER) allele was found to specifically mark all glial and neuron cell types that arise from the ventricular zone (vz). Moreover, each cell type has a unique temporal profile of marking with Ascl1(CreER) GIFM. Of great utility, Purkinje cells (Pcs), an early cohort of Bergmann glia, and four classes of GABAergic interneurons can be genetically birth dated during embryogenesis using Ascl1(CreER) GIFM. Astrocytes and oligodendrocytes, in contrast, express Ascl1(CreER) throughout their proliferative phase in the white matter. Interestingly, the final position each neuron type acquires differs depending on when it expresses Ascl1. Interneurons (including candelabrum) attain a more outside position the later they express Ascl1, whereas Pcs have distinct settling patterns each day they express Ascl1. Second, using a conditional Ascl1 allele, we discovered that Ascl1 is differentially required for generation of most vz-derived cells. Mice lacking Ascl1 in the cerebellum have a major decrease in three types of interneurons with a tendency toward a loss of later-born interneurons, as well as an imbalance of oligodendrocytes and astrocytes. Double-mutant analysis indicates that a related helix-loop-helix protein, Ptf1a, functions with Ascl1 in generating interneurons and Pcs. By fate mapping vz-derived cells in Ascl1 mutants, we further discovered that Ascl1 plays a specific role during the time period when Pcs are generated in restricting vz progenitors from becoming rhombic lip progenitors.
authors.affiliation: Developmental Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA.
authors.forename: Anamaria
authors.initials: A
authors.lastname: Sudarov
authors.forename: Rowena K
authors.initials: RK
authors.lastname: Turnbull
authors.forename: Euiseok J
authors.initials: EJ
authors.lastname: Kim
authors.forename: Melanie
authors.initials: M
authors.lastname: Lebel-Potter
authors.forename: Francois
authors.initials: F
authors.lastname: Guillemot
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Joyner
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D019521:Body Patterning / Q000235:genetics; D001931:Brain Mapping; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D002531:Cerebellum / Q000166:cytology* / Q000196:embryology / Q000254:growth & development; D002552:Cerebral Ventricles / Q000166:cytology / Q000196:embryology; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009415:Nerve Net / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000145:classification / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D011506:Proteins / Q000235:genetics; D022661:RNA, Untranslated; D016622:Silver Staining / Q000379:methods; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D022661:RNA, Untranslated; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid; C499317:Ascl1 protein, mouse; C080330:En1 protein, mouse; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; C062602:transcription factor PTF1