title: Multiplex genetic fate mapping reveals a novel route of neocortical neurogenesis, which is altered in the Ts65Dn mouse model of Down syndrome.
abstract: While several major classes of neocortical neural precursor cells have been identified, the lineal relationships and molecular profiles of these cells are still largely unknown. Furthermore, the individual contribution of each cell class to neocortical growth during normal development and in neurodevelopmental disorders has not been determined. Using a novel fate-mapping approach, we demonstrate that precursors in the embryonic ventricular (VZ) and subventricular zones (SVZ), which give rise to excitatory neurons, are divided into distinct subtypes based on lineage profile, morphology, and transcription factor expression in vivo. Using this technique, we show that short neural precursors are a unique class of VZ intermediate progenitors derived from radial glial cells and are distinct from the multipolar Tbr2((+)) intermediate progenitors, which divide in the SVZ. To test whether these multiple groups of intermediate progenitors are redundant or whether they are necessary for proper neocortical growth, we measured precursor cell diversity in the Ts65Dn mouse model of Down syndrome (DS), which exhibits reduced neurogenesis and postnatal microcephaly. We report that SNP generation is markedly reduced in the Ts65Dn VZ during mid-neurogenesis, indicating that faulty specification of this progenitor pool is a central component of the neocortical abnormality in DS. Together, these findings demonstrate that neocortical neurons are produced via multiple indirect routes during embryonic development and that these parallel streams of neurogenesis collectively contribute to the proper growth and development of the neocortex.
authors.affiliation: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Tyler
authors.forename: Tarik F
authors.initials: TF
authors.lastname: Haydar
mesh_terms: D000818:Animals; D002455:Cell Division / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D017930:Genes, Reporter / Q000502:physiology; D019426:Integrases / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008831:Microcephaly / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D018715:Microscopy, Video; D019579:Neocortex / Q000002:abnormalities* / Q000473:pathology* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics; D058953:Neural Stem Cells / Q000166:cytology / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology*; D009924:Organ Culture Techniques; D011247:Pregnancy; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics
chemical_list: D027341:Excitatory Amino Acid Transporter 1; C086936:Fabp7 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; C493393:Slc1a3 protein, mouse; C090377:pre-T cell receptor alpha; C045073:Cre recombinase; D019426:Integrases