The amino acid G-amino-butyric-acid (GABA) is the major inhibitory neurotransmitter in the mature brain and plays an important role in regulating neuronal activity levels and synaptic plasticity, controlling the formation and propagation of neuronal activity, and generating local and large-scale oscillatory activity. In accordance with these diverse GABAergic functions, different classes of neocortical GABAergic interneurons with specific electrophysiological properties, dendritic morphologies, and axonal projection patterns have been identified and classified. In the mature midbrain, GABAergic neurons are found in several locations and participate in many important brain functions. Knowledge of GABAergic neuron development is highly important for understanding their diversity and function and may provide new approaches to the treatment of neurological and psychiatric disease.
Fig.1 GABAergic and glutamatergic domains and their gene-expression in the developing. (Achim, 2014)
No single transcription factor (TF) involved in patterning, neurogenesis or differentiation of GABAergic neurons is shared by all the GABAergic neuron populations. On the other hand, most of the TFs important for GABAergic neuron development also have functions in other neuronal lineages or cell types.
Function | ||||
Brain region | Spatial patterning and progenitor specification HD or bHLH proteins | Proneural genes and their regulators bHLH proteins | Postmitotic subtype selection HD, bHLH, ZF | Maturation, migration, maintenance HLH, HD, ZF |
Telencephalon |
MGE: NKX2-1 LGE, CGE: GSX1/2 POA: NKX5-1 POA: DBX1 DLX1/2 |
ASCL1 |
DLX2 DLX5/6 |
ARX DLX5/6 NR2F2 LHX6 |
Diencephalon |
NKX2-2 FEZF1/2 GBX2 PAX6 |
ASCL1 p1-2: HELT |
p3: DLX2 p1-2: GATA2 p1-2: TAL2 |
p1-2: SOX14 TAL1 GATA3 |
Midbrain |
NKX2-2 NKX6-1 PAX3/7 |
ASCL1 HELT |
GATA2 TAL2 |
PITX2 GATA3 TAL1 LHX1/5 |
Ventral R1 | NKX6-1 |
ASCL1 NGN1/2 |
TAL1 |
TAL1 PITX2 |
Dorsal R1 (cerebellum) |
EN2 PTF1A |
ASCL1 NGN1/2 |
PTF1A |
LHX1/5 NGN1/2 CORL, PAX2 |
Dorsal spinal cord |
dP4: GSX1/2 dP6: DBX2 PAX2 |
dP4: GSX1/2 NGN1/2 |
dI4, dIL, dI6: LBX1 dI4, dIL: PTF1A |
LBX1 LHX1/5 |
Ventral spinal cord |
NKX6-1 V0-1: DBX1/2 |
ASCL1 NGN1/2 V2: FOXN4 |
V2b: TAL1 GATA2 LMO4 V0d: EVX1- |
GATA3 LMO4 V1: EN1 |
Mutant phenotype (mouse) | GABAergic progenitors mispatterned or missing | GABAergic neurogenesis delayed and/or diminished | GABAergic precursors respecified to alternative fate | Incomplete differentiation/ impaired functionality |
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Reference
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