Pax6 Is Essential for the Maintenance and Multi-Lineage Differentiation of Neural Stem Cells, and for Neuronal Incorporation into the Adult Olfactory Bulb

Abstract

The paired type homeobox 6 (Pax6) transcription factor (TF) regulates multiple aspects of neural stem cell (NSC) and neuron development in the embryonic central nervous system. However, less is known about the role of Pax6 in the maintenance and differentiation of adult NSCs and in adult neurogenesis. Using the + /Sey Dey mouse, we have analyzed how Pax6 heterozygosis influences the self-renewal and proliferation of adult olfactory bulb stem cells (aOBSCs). In addition, we assessed its influence on neural differentiation, neuronal incorporation, and cell death in the adult OB, both in vivo and in vitro. Our results indicate that the Pax6 mutation alters Nestin + -cell proliferation in vivo, as well as self-renewal, proliferation, and survival of aOBSCs in vitro although a subpopulation of + /Sey Dey progenitors is able to expand partially similar to wild-type progenitors. This mutation also impairs aOBSC differentiation into neurons and oligodendrocytes, whereas it increases cell death while preserving astrocyte survival and differentiation. Furthermore, Pax6 heterozygosis causes a reduction in the variety of neurochemical interneuron subtypes generated from aOBSCs in vitro and in the incorporation of newly generated neurons into the OB in vivo. Our findings support an important role of Pax6 in the maintenance of aOBSCs by regulating cell death, self-renewal, and cell fate, as well as in neuronal incorporation into the adult OB. They also suggest that deregulation of the cell cycle machinery and TF expression in aOBSCs which are deficient in Pax6 may be at the origin of the phenotypes observed in this adult NSC population.

A Primitive Growth Factor, NME7AB, Is Sufficient to Induce Stable Naïve State Human Pluripotency; Reprogramming in This Novel Growth Factor Confers Superior Differentiation

“…Notably, the subset of genes that all three studies agreed were downregulated comprised a DAVID cluster involved in patterning, cell migration and urogenital development. This group included GREM1 , DUSP6 , CAV1 , and SFRP1 , which are involved in MAP kinase, BMP, and Wnt signaling , as well as SOX17 , LHX1 , STMN2 , PAX6 , and LIN7a , which are involved in differentiation .…”

PAX6, brain structure and function in human adults: advanced MRI in aniridia

“…It is also now increasingly appreciated that gene regulatory programs launched early in fetal life to specify neuronal‐type identities, continue to function later in life to maintain postmitotic identities . Indeed, animal models have demonstrated the persistence of Pax6 expression, and its role in the generation of neural stem progenitor cells and maintenance of neurogenic fate in the adult rodent brain. Ninkovic et al demonstrated that ongoing expression of Pax6 in mature healthy brain is intrinsically required for the survival of dopaminergic neurons in the olfactory bulb through maintenance of crystalline α A expression, which prevents caspase‐3‐mediated programmed cell death .…”

Brain Insulin-Like Growth Factor-I Directs the Transition from Stem Cells to Mature Neurons During Postnatal/Adult Hippocampal Neurogenesis

“…After six DIV the cells were recovered for RNA extraction followed by real‐time reverse transcription quantitative‐polymerase chain reaction (RT‐qPCR) analysis using the primers listed in Supporting Information Table S3. Then, gene expression changes Igf‐I Δ/Δ mice were compared relative to the levels of gene expression obtained in Igf‐I Ctrl mice, using the CT method and were expressed as fold changes in log2 scale. The expression of Igf‐I in HPSCs, olfactory bulb stem cells (OBSCs), fibroblasts and hepatocytes obtained from Igf‐I Ctrl and Igf‐I Δ/Δ mice was also measured by (RT‐qPCR) and the results were given as relative mRNA levels normalized to the Ct value for Gapdh .…”