Abstract
SummaryMidbrain- and hindbrain-derived GABAergic interneurons are critical for regulation of sleep, respiratory, sensory-motor and motivational processes, and they are implicated in human neurological disorders. However, the precise mechanisms that underlie generation of GABAergic neuron diversity in the midbrain–hindbrain region are poorly understood. Here, we show unique and overlapping requirements for the related bHLH proteins Tal1 and Tal2 in GABAergic neurogenesis in the midbrain. We show that Tal2 and Tal1 are specifically and sequentially activated during midbrain GABAergic neurogenesis. Similar to Gata2, a post-mitotic selector of the midbrain GABAergic neuron identity, Tal2 expression is activated very early during GABAergic neuron differentiation. Although the expression of Tal2 and Gata2 genes are independent of each other, Tal2 is important for normal midbrain GABAergic neurogenesis, possibly as a partner of Gata2. In the absence of Tal2, the majority of midbrain GABAergic neurons switch to a glutamatergic-like phenotype. In contrast, Tal1 expression is activated in a Gata2 and Tal2 dependent fashion in the more mature midbrain GABAergic neuron precursors, but Tal1 alone is not required for GABAergic neuron differentiation from the midbrain neuroepithelium. However, inactivation of both Tal2 and Tal1 in the developing midbrain suggests that the two factors co-operate to guide GABAergic neuron differentiation in a specific ventro-lateral midbrain domain. The observed similarities and differences between Tal1/Tal2 and Gata2 mutants suggest both co-operative and unique roles for these factors in determination of midbrain GABAergic neuron identities.
Highlights
The mammalian midbrain and hindbrain contain neuronal populations that control motivation, motor and sensory function as well as vital autonomic activity and sleep.Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the mature brain and is used by hundreds of different types of neurons throughout the central nervous system (CNS)
Tal1 expression is activated in a Gata2 and Tal2 dependent fashion in the more mature midbrain GABAergic neuron precursors, but Tal1 alone is not required for GABAergic neuron differentiation from the midbrain neuroepithelium
These precursors are thought to contribute to diversified GABAergic neurons in the midbrain including superior and inferior colliculi, periaqueductal gray area and nuclei in the midbrain reticular formation, where they are involved in functions such as processing of sensory information (Tsunekawa et al, 2005; Kala et al, 2009; Peltopuro et al, 2010; Lahti et al, 2013)
Summary
The mammalian midbrain and hindbrain contain neuronal populations that control motivation, motor and sensory function as well as vital autonomic activity and sleep.Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the mature brain and is used by hundreds of different types of neurons throughout the central nervous system (CNS). Distinct GABAergic precursors are generated in ventro-lateral and dorsal progenitor domains m1–m5 (Nakatani et al, 2007; Kala et al, 2009) These precursors are thought to contribute to diversified GABAergic neurons in the midbrain including superior and inferior colliculi, periaqueductal gray area and nuclei in the midbrain reticular formation (mRF), where they are involved in functions such as processing of sensory information (Tsunekawa et al, 2005; Kala et al, 2009; Peltopuro et al, 2010; Lahti et al, 2013). Other GABAergic neurons associate with dopaminergic (DA) nuclei, ventral tegmental area (VTA) and substantia nigra (SN), in the ventral midbrain These ventral midbrain GABAergic neurons (vMB GABAn) are critical for the activity of the DA pathways and regulation of voluntary movements. The GABAergic neurons in the diencephalic part of SN
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