Origin of GABAergic neurons in the human neocortex.
The mammalian neocortex contains two major classes of neurons, projection and local circuit neurons. Projection neurons contain the excitatory neurotransmitter glutamate, while local circuit neurons are inhibitory, containing GABA. The complex function of neocortical circuitry depends on the number and diversity of GABAergic (gamma-aminobutyric-acid-releasing) local circuit neurons. Using retroviral labelling in organotypic slice cultures of the embryonic human forebrain, we demonstrate the existence of two distinct lineages of neocortical GABAergic neurons. One lineage expresses Dlx1/2 and Mash1 transcription factors, represents 65% of neocortical GABAergic neurons in humans, and originates from Mash1-expressing progenitors of the neocortical ventricular and subventricular zone of the dorsal forebrain. The second lineage, characterized by the expression of Dlx1/2 but not Mash1, forms around 35% of the GABAergic neurons and originates from the ganglionic eminence of the ventral forebrain. We suggest that modifications in the expression pattern of transcription factors in the forebrain may underlie species-specific programmes for the generation of neocortical local circuit neurons and that distinct lineages of cortical interneurons may be differentially affected in genetic and acquired diseases of the human brain.
Letinic
Kresimir
K
Yale University School of Medicine, Section of Neurobiology, New Haven, Connecticut 06510, USA.
Zoncu
Roberto
R
Rakic
Pasko
P
D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers / Q000032:analysis; D002455:Cell Division; D019070:Cell Lineage; D002465:Cell Movement; D003094:Collagen; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins / Q000032:analysis; D004338:Drug Combinations; D018398:Homeodomain Proteins / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007395:Interneurons / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D007797:Laminin; D008854:Microscopy, Electron; D019579:Neocortex / Q000166:cytology* / Q000196:embryology / Q000378:metabolism* / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D011509:Proteoglycans; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism; D016601:RNA-Binding Proteins; D013045:Species Specificity; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D014157:Transcription Factors / Q000032:analysis; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D003094:Collagen; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D018398:Homeodomain Proteins; D007797:Laminin; D011509:Proteoglycans; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid; C065500:ASCL1 protein, human; C088334:Distal-less homeobox proteins; C093661:Tes protein, mouse; C059485:matrigel