Zic-Proteins Are Repressors of Dopaminergic Forebrain Fate in Mice andC. elegans

Abstract

In the postnatal forebrain regionalized neural stem cells along the ventricular walls produce olfactory bulb (OB) interneurons with varying neurotransmitter phenotypes and positions. To understand the molecular basis of this region-specific variability we analyzed gene expression in the postnatal dorsal and lateral lineages in mice of both sexes from stem cells to neurons. We show that both lineages maintain transcription factor signatures of their embryonic site of origin, the pallium and subpallium. However, additional factors, including Zic1 and Zic2, are postnatally expressed in the dorsal stem cell compartment and maintained in the lineage that generates calretinin-positive GABAergic neurons for the OB. Functionally, we show that Zic1 and Zic2 induce the generation of calretinin-positive neurons while suppressing dopaminergic fate in the postnatal dorsal lineage. We investigated the evolutionary conservation of the dopaminergic repressor function of Zic proteins and show that it is already present in The vertebrate brain generates thousands of different neuron types. In this work we investigate the molecular mechanisms underlying this variability. Using a genomics approach we identify the transcription factor signatures of defined neural stem cells and neuron populations. Based thereon we show that two related transcription factors, Zic1 and Zic2, are essential to control the balance between two defined neuron types in the postnatal brain. We show that this mechanism is conserved in evolutionary very distant species.

Characterization of perinatally born glutamatergic neurons of the mouse olfactory bulb based on NeuroD6 expression reveals their resistance to sensory deprivation

“…The anti-TH antibody recognized the TH which is specifically expressed in dopaminergic neurons. This antibody stained a subpopulation of mature neurons in the glomerular layer of the olfactory bulb in a pattern similar that has been observed in previous studies (de Chevigny et al, 2012;Qin, Ware, Waclaw, & Campbell, 2017;Tiveron et al, 2017).…”

“…With the anti‐CalR and anti‐CalB antibodies, we stained two specific sub‐populations of mature neurons within the glomerular layer of the olfactory bulb with a similar pattern as obtained in previous studies (de Chevigny et al, ; Tiveron et al, ).…”

“…To induce a control cohort of mostly GABAergic JGCs, for which deprivation‐sensitivity has been demonstrated, we performed postnatal (P0) electroporation of a Cre expressing DNA plasmid into the dorsal ventricular wall of Rosa26 tdTomato mice. This approach labeled a mixed population of GABAergic and GABA/dopaminergic JGCs but only scarcely glutamatergic JGCs (Tiveron et al, ). In parallel, we induced postnatally born cohorts of tdTom expressing glutamatergic JGCs by TAM injection in ND6 CreERT2/tdTom mice at P0.…”

Regulatory interactions between Vax1, Pax6, and miR-7 regionalize the lateral Ventricular-Subventricular Zone during post-natal Olfactory Bulb neurogenesis in mice

“…Vax1 mRNA was induced at low levels at 1 day postelectroporation (dpe) when most GFP positive cells were transit amplifying precursors [TAPs, (Boutin et al, 2008); Figure 1B]. Expression strongly increased at 2dpe and remained stably high at 4dpe, when most cells were migratory neuronal precursors, before steeply decreasing at 7dpe when cells arrived in the OB and emigrated from the RMS to invade the granule cell (GCL) and the glomerular (GL) layers (Tiveron et al, 2017). In comparison, isolates from dorsally electroporated brains showed no obvious Vax1 mRNA expression over all analyzed time points ( Figure 1B).…”

“…It has been shown that Gli1 activation by Sonic Hedgehog (SHH) is necessary to generate Calbindin-expressing periglomerular neurons (CB-N) in the ventral aspect (Ihrie et al, 2011). Moreover, the zincfinger transcription factors (TF) Zic1 and Zic2 act as inducers of Calretinin (CR)-expressing GABAergic interneurons in the dorso-septal region (Tiveron et al, 2017). However, the high diversity of the postnatal generated interneuron subtypes suggests that more complex molecular cascades and cross regulatory interactions are put in place to define the stem cell compartment at the necessary resolution.…”