Cell-Biological Requirements for the Generation of Dentate Gyrus Granule Neurons

Abstract

The dentate gyrus (DG) receives highly processed information from the associative cortices functionally integrated in the trisynaptic hippocampal circuit, which contributes to the formation of new episodic memories and the spontaneous exploration of novel environments. Remarkably, the DG is the only brain region currently known to have high rates of neurogenesis in adults (Andersen et al., 1966, 1971). The DG is involved in several neurodegenerative disorders, including clinical dementia, schizophrenia, depression, bipolar disorder and temporal lobe epilepsy. The principal neurons of the DG are the granule cells. DG granule cells generated in culture would be an ideal model to investigate their normal development and the causes of the pathologies in which they are involved and as well as possible therapies. Essential to establish such in vitro models is the precise definition of the most important cell-biological requirements for the differentiation of DG granule cells. This requires a deeper understanding of the precise molecular and functional attributes of the DG granule cells in vivo as well as the DG cells derived in vitro. In this review we outline the neuroanatomical, molecular and cell-biological components of the granule cell differentiation pathway, including some growth- and transcription factors essential for their development. We summarize the functional characteristics of DG granule neurons, including the electrophysiological features of immature and mature granule cells and the axonal pathfinding characteristics of DG neurons. Additionally, we discuss landmark studies on the generation of dorsal telencephalic precursors from pluripotent stem cells (PSCs) as well as DG neuron differentiation in culture. Finally, we provide an outlook and comment critical aspects.

Neurogenesis From Embryo to Adult – Lessons From Flies and Mice

“…Recent data suggest that an early cohort of Tbr2 INPs expressing Notch ligands pioneers the subsequent NSC migration toward the newly formed outer (abventricular) SGZ niche, keeping neighboring NSCs in an undifferentiated state through Notch signaling (Nelson et al, 2020). The regional identity of SGZ NSCs is markedly influenced by a number of other transcription factors (Hatami et al, 2018), including Emx2 and Lef1 (Pellegrini et al, 1996;Galceran et al, 2000;Oldekamp et al, 2004), as well as by Wnt and bone morphogenetic protein signaling from the adjacent cortical hem (Li and Pleasure, 2007). Interestingly, the transcription factor sequence Pax6 → Ngn2 → Tbr2 → NeuroD → Tbr1 observed in developmental glutamatergic neurogenesis in the cortex is conserved along the lineage progression of adult SGZ neurogenesis (Figure 3; Hodge et al, 2008;Roybon et al, 2009b).…”

Dendritic morphology and inhibitory regulation distinguish dentate semilunar granule cells from granule cells through distinct stages of postnatal development

“…In this context, studies examining dendritic properties of GCs with somata located in the outer third of the molecular layer have consistently reported wider dendritic fields and distinct dendritic arbors consistent with the possibility that the outer third of the granule cell layer may consist of a mixed population of GCs and SGCs (Green and Juraska 1985;Kerloch et al 2018;Sun et al 2013). Whether specific genetic, molecular or developmental cues guide the development of SGCs during neurogenesis or whether local molecular and spatial factors in the dentate GCL-molecular layer border contribute to elaboration of distinct dendritic arbors remains to be determined (Hatami et al 2018;Lefebvre et al 2015).…”

Dendritic Morphology and Inhibitory Regulation Distinguish Dentate Semilunar Granule Cells from Granule Cells through Distinct Stages of Postnatal Development

“…In this context, studies examining dendritic properties of GCs with somata located in the outer third of the molecular layer have consistently reported wider dendritic fields and distinct dendritic arbors consistent with the possibility that the outer third of the granule cell layer may consist of a mixed population of GCs and SGCs (Green and Juraska 1985; Kerloch et al 2018; Sun et al 2013). Whether specific genetic, molecular or developmental cues guide the development of SGCs during neurogenesis or whether local molecular and spatial factors in the dentate GCL-molecular layer border contribute to elaboration of distinct dendritic arbors remains to be determined (Hatami et al 2018; Lefebvre et al 2015). Similarly, whether SGCs and GCs have comparable dendritic length distribution within the distinct axonal projection zones, namely, commissural/associational pathway in the IML, medial perforant path in the middle molecular layer and lateral perforant path in the outer molecular layer was outside the scope of the current study and merits further analysis.…”