Gata2, Nkx2-2 and Skor2 form a transcription factor network regulating development of a midbrain GABAergic neuron subtype with characteristics of REM-sleep regulatory neurons

Abstract

The midbrain reticular formation is a mosaic of diverse GABAergic and glutamatergic neurons that have been associated with a variety of functions, including the regulation of sleep. However the molecular characteristics and development of the midbrain reticular formation neurons are poorly understood. As the transcription factor Gata2 is required for the development of all GABAergic neurons derived from the embryonic mouse midbrain, we hypothesized that the genes expressed downstream of Gata2 could contribute to the diversification of GABAergic neuron subtypes in this brain region. Here, we show that Gata2 is indeed required for the expression of several lineage-specific transcription factors in post-mitotic midbrain GABAergic neuron precursors. These include a homeodomain transcription factor Nkx2-2 and a SKI family transcriptional repressor Skor2, which are co-expressed in a restricted group of GABAergic precursors in the midbrain reticular formation. Both Gata2, and Nkx2-2 function is required for the expression of Skor2 in GABAergic precursors. In the adult mouse as well as rat midbrain, the Nkx2-2 and Skor2 expressing GABAergic neurons locate at the boundary of the ventrolateral periaqueductal gray and the midbrain reticular formation, an area shown to contain REM-off neurons regulating REM sleep. In addition to the characteristic localization, the Skor2 positive cells increase their activity upon REM sleep inhibition, send projections to the dorsolateral pons, a region associated with sleep control, and are responsive to orexins, consistent with the known properties of the midbrain REM-off neurons.

Mapping Somatosensory Afferent Circuitry to Bone Identifies Neurotrophic Signals Required for Fracture Healing

“…At d1 post-fracture, Zfp263 , Nfkb2 and Stat1 were significantly upregulated, TFs associated with the regulation of inflammation in other systems ( Nfkb2 and Stat1 21–23 ). At d14 post-fracture, several TFs were identified, including regulators of neural development ( Maz and Gata2) 24,25 , NGF target genes ( Egr3 ) 26,27 , negative regulators of neuronal apoptosis ( Klf2 ) 28 , as well as stress-responsive genes ( Atf4 ) 29 . Interestingly, common neuronal markers of nerve injury (e.g.…”

Neuronal PAS domain 1 identifies a major subpopulation of wakefulness-promoting GABAergic neurons in basal forebrain

“…Furthermore, as far as we are aware, this is the first study to examine the sleep-wake function of a subgroup of BF neurons based on a developmental lineage marker, emphasizing the usefulness of developmental transcription factors in identifying novel subpopulations of sleep-wake control neurons (Liu et al, 2017;Kirjavainen et al, 2022).…”

“…Identification of this major population of wakefulness-promoting BF GABAergic neurons will allow new studies of their role in sleep disorders, dementia and other neuropsychiatric conditions affecting the BF. Furthermore, as far as we are aware, this is the first study to examine the sleep-wake function of a subgroup of BF neurons based on a developmental lineage marker, emphasizing the usefulness of developmental transcription factors in identifying novel subpopulations of sleep-wake control neurons (Liu et al, 2017; Kirjavainen et al, 2022).…”

“…An approach that has been productive in defining subpopulations of cerebral cortex GABAergic interneurons (Lim et al, 2018) and subpopulations of GABAergic projection neurons in the basal ganglia (Hernandez et al, 2015; Abecassis et al, 2020; Cui et al, 2021) is the use of developmental transcription factors to serve as markers for specific neuronal populations. This approach has also been fruitful in identifying novel sleep-wake populations in the hypothalamus (Liu et al, 2017) and brainstem (Kirjavainen et al, 2022), but has so far not been applied to the basal forebrain (BF), a key brain region involved in the control of sleep-wake behavior, cortical activation, attention, and motivation (Detari et al, 1999; Zaborszky and Duque, 2003; Brown et al, 2012; Brown and McKenna, 2015; Lin et al, 2015; Morais-Silva et al, 2023) which degenerates in dementia patients (Grothe et al, 2014; Pereira et al, 2020) and is dysregulated in various psychiatric disorders (McNally et al, 2021; Morais-Silva et al, 2023; Soares-Cunha & Heinsbroek 2023).…”