Abstract
The complex structure and function of the cerebral cortex critically depend on the balance of excitation and inhibition provided by the pyramidal projection neurons and GABAergic interneurons, respectively. The calretinin-expressing (CalR+) cell is a subtype of GABAergic cortical interneurons that is more prevalent in humans than in rodents. In rodents, CalR+ interneurons originate in the caudal ganglionic eminence (CGE) from Gsx2+ progenitors, but in humans it has been suggested that a subpopulation of CalR+ cells can also be generated in the cortical ventricular/subventricular zone (VZ/SVZ). The progenitors for cortically generated CalR+ subpopulation in primates are not yet characterized. Hence, the aim of this study was to identify patterns of expression of the transcription factors (TFs) that commit cortical stem cells to the CalR fate, with a focus on Gsx2. First, we studied the expression of Gsx2 and its downstream effectors, Ascl1 and Sp8 in the cortical regions of the fetal human forebrain at midgestation. Next, we established that a subpopulation of cells expressing these TFs are proliferating in the cortical SVZ, and can be co-labeled with CalR. The presence and proliferation of Gsx2+ cells, not only in the ventral telencephalon (GE) as previously reported, but also in the cerebral cortex suggests cortical origin of a subpopulation of CalR+ neurons in humans. In vitro treatment of human cortical progenitors with Sonic hedgehog (Shh), an important morphogen in the specification of interneurons, decreased levels of Ascl1 and Sp8 proteins, but did not affect Gsx2 levels. Taken together, our ex-vivo and in vitro results on human fetal brain suggest complex endogenous and exogenous regulation of TFs implied in the specification of different subtypes of CalR+ cortical interneurons.
Highlights
The increased complexity of cortical progenitors is considered to be an evolutionary adaptation necessary for the development of higher brain functions in primates, and in humans
room temperature (RT)-PCR demonstrated that genomic screened homeobox 2 (Gsx2) mRNA levels in the GE at 16 and 18 gw were 345 folds and 104 folds higher respectively compared to the cortex
In addition to regional differences, Gsx2 expression in the human fetal brain seems to vary with gestational age, this point needs to be confirmed on more cases
Summary
The increased complexity of cortical progenitors is considered to be an evolutionary adaptation necessary for the development of higher brain functions in primates, and in humans. In contrast to rodents, where the majority, if not all, cortical interneurons are generated in the ventral telencephalon (ganglionic eminence, GE; Anderson et al, 1997; Tamamaki et al, 1997; Parnavelas, 2000; Marin and Rubenstein, 2001), several groups have reported that cortical interneurons in primates originate both ventrally (in the GE) and dorsally, in the cortical subventricular zone (SVZ; Letinic et al, 2002; Rakic and Zecevic, 2003; Petanjek et al, 2009b; Jakovcevski et al, 2011; Al-Jaberi et al, 2013) This topic is still open for discussion since other groups reported that similar to rodents, the majority of cortical interneurons in primates originate in the GE and no proliferation of interneuron progenitors was demonstrated in the cortex (Hansen et al, 2013; Ma et al, 2013)
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