NFIX-Mediated Inhibition of Neuroblast Branching Regulates Migration Within the Adult Mouse Ventricular–Subventricular Zone

Abstract

Understanding the migration of newborn neurons within the brain presents a major challenge in contemporary biology. Neuronal migration is widespread within the developing brain but is also important within the adult brain. For instance, stem cells within the ventricular–subventricular zone (V-SVZ) and the subgranular zone of dentate gyrus of the adult rodent brain produce neuroblasts that migrate to the olfactory bulb and granule cell layer of the dentate gyrus, respectively, where they regulate key brain functions including innate olfactory responses, learning, and memory. Critically, our understanding of the factors mediating neuroblast migration remains limited. The transcription factor nuclear factor I X (NFIX) has previously been implicated in embryonic cortical development. Here, we employed conditional ablation of Nfix from the adult mouse brain and demonstrated that the removal of this gene from either neural stem and progenitor cells, or neuroblasts, within the V-SVZ culminated in neuroblast migration defects. Mechanistically, we identified aberrant neuroblast branching, due in part to increased expression of the guanylyl cyclase natriuretic peptide receptor 2 (Npr2), as a factor contributing to abnormal migration in Nfix-deficient adult mice. Collectively, these data provide new insights into how neuroblast migration is regulated at a transcriptional level within the adult brain.

Heterozygosity for Nuclear Factor One X in mice models features of Malan syndrome

“…Interestingly, NFIX is expressed by neurons in each of the six layers of the cortical plate of the adult mouse neocortex [16], however, the role of NFIX in these mature neuronal populations has not been investigated. Recently, we have shown that NFIX is a crucial mediator within the adult NSC populations of the hippocampus [17] and ventricular-subventricular zone [18] of the mature mouse brain. In contrast, Nfix heterozygous ( Nfix +/− ) mice survive until adulthood [9,11] making them an ideal model to investigate brain size and connectivity as a proxy for Malan syndrome.…”

Molecular mechanisms underlying malformations of cortical development

“…Nfix shRNA treated neuroblasts also migrated significantly less than controls (Fig. 3.10D, E), which is in accordance with previous studies showing absence of Nfix leading to migrational defects in neuroblasts (Heng et al, 2015;Zalucki et al, 2019). However, it should be noted that while biological sample triplicates were performed for this assay, more experiments are needed to confirm these results.…”

“…Moreover, NFIX plays a vital role in the adult NSC populations of the hippocampus ) and SVZ (Heng et al, 2015;Zalucki et al, 2019) of the mature mouse brain. NFIX is expressed by adult hippocampal NSCs and most highly in neuroblasts of the hippocampal dentate gyrus .…”

“…Additionally, it was revealed that a small proportion of adult hippocampal NSCs, that were Nfix-deficient, produced oligodendrocytes, while Nfix-deficient IPCs and neuroblasts had morphological defects and increased mRNA expression of oligodendrocyte precursor genes . In the adult SVZ, absence of Nfix from adult NSCs and progenitor cells led to abnormal neuroblast migration underlined, in part, by excessive neuroblast branching and increased expression of the guanylyl cyclase natriuretic peptide receptor 2 (Npr2) (Zalucki et al, 2019).…”

Alterations in gene expression in the spinal cord of mice lacking Nfix

“…For example, the Nuclear Factor One (NFI) transcription factors regulate fetal muscle gene expression [ 1 ], retinal development [ 2 ], and dorsal telencephalic formation [ 3 , 4 ]. NFIX specifically promotes neural stem cell differentiation within the developing neocortex, hippocampus and cerebellum [ 5 – 8 ], as well as within the adult forebrain neurogenic niches [ 9 , 10 ]. Mechanistically, NFIs have been shown to drive differentiation within the nervous system via the activation of lineage-specific gene expression patterns, as well as via the repression of stem cell self-renewal genes [ 11 , 12 ].…”