Multiple Origins of Human Neocortical Interneurons Are Supported by Distinct Expression of Transcription Factors

Abstract

Cortical γ-aminobutyric acid (GABA)ergic interneurons in rodents originate mainly in ventrally positioned ganglionic eminences (GEs), but their origin in primates is still debated. We studied human fetal forebrains during the first half of gestation (5-23 gestational weeks, gw) for the expression of ventral transcription factors, Nkx2.1, Dlx1,2, Lhx6, and Mash1, important for development of neocortical interneurons. In embryonic (5-8 gw) human forebrain, these factors were expressed in the GE but also dorsally in the neocortical ventricular/subventricular zones (VZ/SVZ). Furthermore, their expression was retained in cells of all fetal cortical layers up to midgestation (20 gw). Nkx2.1 continued to be expressed not only in the GE but also in a subpopulation of neocortical interneurons. Moreover, proliferation marker Ki67 revealed that calretinin(+), Mash1(+), and Nkx2.1(+) cells proliferate in the neocortical VZ/SVZ at midgestation. At least some of the Mash1(+) progenitors in the neocortical SVZ could be colabeled with GABA, whereas others were oligodendrocyte progenitors, indicating a link between the 2 lineages. Taken together, these results suggest the existence of several categories of dorsal interneuronal progenitors in the human neocortical VZ/SVZ, in addition to ventrally derived cortical interneurons described in rodents. These human-specific developmental events may underlie human brain's higher complexity and capacity to process information.

Secretagogin is Expressed by Developing Neocortical GABAergic Neurons in Humans but not Mice and Increases Neurite Arbor Size and Complexity

“…For example, interneurons expressing tyrosine hydroxylase appear to be particularly abundant in deep layers of human neocortex relative to other mammalian species (Defelipe 2011). Variation in GABAergic neuron subtype proportions between human and mouse neocortex has also been attributed to species' differences in the neuroanatomical origins of these cells (Letinic et al 2002;Jakovcevski et al 2011;Yu and Zecevic 2011;Radonjic et al 2014a), although this interpretation is not universally accepted (Hansen et al 2013;Ma et al 2013). Our finding of molecular differences in SCGN activity between humans and mice provides further support for efforts to clarify species' differences among subpopulations of GABAergic neurons.…”

“…However, there is no molecular explanation for morphological differences in VIP + /CR + neocortical GABAergic neurons between rodents and primates. Indeed, although several studies have examined the origins and development of human GABAergic neurons (Bayatti et al 2008;Jakovcevski et al 2011;Radonjic et al 2014b;Al-Jaberi et al 2015), to our knowledge, no molecular differences between GABAergic neurons of rodents and primates have been described. Given the increasing appreciation for the role of GABAergic dysfunction in a variety of human neurodevelopmental disorders (Marin 2012;Southwell et al 2014), it is critical to understand the molecular bases of GABAergic neuron specification and maturation in the human brain (Clowry et al 2010;Molnar and Clowry 2012).…”

Development of Cortical Interneurons

“…Alternatively, GABAergic neurons could be imported into the evolving cortex from more ventrally located parts of the neural tube that were already producing these cells. Evolution chose importation, and although there has been some support for the notion that cortical LCN origins in primates may include the cortex itself (Jakovcevski et al, 2011;Letinic et al, 2002;Yu and Zecevic, 2011), the bulk of cortical LCN neurogenesis in humans and other primates occurs in the ventral, subcortical forebrain (Hansen et al, 2013;Ma et al, 2013). The following section discusses the main spatial and temporal origins of cortical LCNs, based mainly on studies in rodents, and their relationship with LCN subgroup fate.…”

Detailed Expression Analysis of Regulatory Genes in the Early Developing Human Neural Tube

“…In recent years, there are a growing number of online public resources [eg, Allen Brain Atlas (www.brain-map.org); HUDSEN (www.hudsen.org)] providing human brain region specific transcriptome profiling and/or in situ hybridization of the human CNS, which doubtless will advance the field. However, combinatorial gene expression studies with cellular resolution in human at stages when neuronal subtype specification takes place (3-7 weeks) are still very few [11][12][13].…”