Pax6 Regulates Cell Adhesion during Cortical Development

Abstract

Pax6 is a member of an evolutionarily conserved family of transcription factors. It is developmentally regulated and is required for the normal embryonic development of the central nervous system, eye and pancreas. Pax6 mutations in the mouse result in the Small eye (Sey) phenotype. Heterozygous mice have eye defects and homozygotes die immediately after birth lacking eyes, nasal cavities and with severe brain abnormalities, including a malformed cerebral cortex. Recent work has established that there are changes in expression of cell adhesion molecules and these may underlie at least a part of the Pax6(Sey/Sey) phenotype. Here we used cell transplants and explant cultures to investigate the role of Pax6 in cell adhesion. Pax6(Sey/Sey) embryonic cortical cells transplanted into wild-type embryonic cortex were observed to segregate from wild-type cells and form dense clusters. Cells migrating from explants of Pax6(Sey/Sey) embryonic cortex clustered to a greater extent than cells migrating from wild-type controls. These new data support the hypothesis that Pax6 exerts a cell-autonomous effect on the adhesiveness of cortical cells.

A novel role for Pax6 in the segmental organization of the hindbrain

“…In such a scenario, the expected phenotypes of excess or reduced Pax6 levels will include enhanced or reduced adhesion of r3/r5 cells, their segregation or spreading, respectively, and prevention of sharp segmental borders and boundary cell formation, as we indeed demonstrated. Pax6 regulates adhesion molecules in the CNS, such as L1, tenascin and cadherins (Duparc et al, 2006;Osumi, 2001;Osumi et al, 2008;Stoykova et al, 1997;Takahashi and Osumi, 2011;Tyas et al, 2003). As some of these adhesion molecules are expressed in the hindbrain (Liu et al, 2001;Numayama-Tsuruta et al, 2010;Takahashi and Osumi, 2008), it would be of interest to test whether Pax6 controls their expression at early stages.…”

Imbalance of excitatory/inhibitory synaptic protein expression in iPSC-derived neurons from FOXG1+/− patients and in foxg1+/− mice

“…FOXG1 overexpression inhibits gliogenesis and promotes neurogenesis in Neural-Stem Cells (NSCs); in fact, it can reprogram fibroblasts into Neural-precursor-like cells when paired with PAX6 overexpression 16, 17 . On top of this, FoxG1 directly controls the levels of PAX6, another transcription factor equally important for promoting neural stem cell proliferation and inhibiting premature neuronal differentiation during early forebrain development 18-25 .…”

Retinal patterning by Pax6‐dependent cell adhesion molecules

“…In the absence of functional Pax6 protein, cytoarchitectonic alterations, failure of cell migration and altered cell adhesion, occur in the developing cortex and ganglia (Stoykova et al, 1997;Chapouton et al, 1999;Kawano et al, 1999;Jimenez et al, 2002;Tyas et al, 2003). Pax6 deficiency may be accompanied by disturbed expression of extracellular matrix components such as reelin , axonal guidance molecules such as semaphorins and netrin (Jones et al, 2002) and cell adhesion molecules (CAM) such as L1-CAM (Kawano et al, 1999) and R-cadherin (Stoykova et al, 1997).…”