Sall1 regulates cortical neurogenesis and laminar fate specification, implications for neural abnormalities in Townes Brocks Syndrome

Abstract

SUMMARYProgenitor cells in the cerebral cortex undergo dynamic cellular and molecular changes during development. Sall1 is a putative transcription factor that is highly expressed in progenitor cells during development. In humans, the autosomal dominant developmental disorder Townes-Brocks syndrome (TBS) is associated with mutations of the SALL1 gene. TBS is characterized by renal, anal, limb and auditory abnormalities. Although neural deficits have not been recognized as a diagnostic characteristic of the disease, ∼10% of patients exhibit neural or behavioral abnormalities. We demonstrate that, in addition to being expressed in peripheral organs, Sall1 is robustly expressed in progenitor cells of the central nervous system in mice. Both classical- and conditional-knockout mouse studies indicate that the cerebral cortex is particularly sensitive to loss of Sall1. In the absence of Sall1, both the surface area and depth of the cerebral cortex were decreased at embryonic day 18.5 (E18.5). These deficiencies are associated with changes in progenitor cell properties during development. In early cortical progenitor cells, Sall1 promotes proliferative over neurogenic division, whereas, at later developmental stages, Sall1 regulates the production and differentiation of intermediate progenitor cells. Furthermore, Sall1 influences the temporal specification of cortical laminae. These findings present novel insights into the function of Sall1 in the developing mouse cortex and provide avenues for future research into potential neural deficits in individuals with TBS.

Temporal fate specification and neural progenitor competence during development

“…It is possible that Cux2 may function differently in VZ and SVZ progenitors or may change its function over time. This appears to be the case for the zinc-finger transcription factor, Sal1, which is highly expressed in cortical progenitors but downregulated in differentiating neurons 67 . In Sal1 knockout mice, progenitors in the early stages of corticogenesis, predominantly the VZ radial glial cells, prematurely exit the cell cycle and differentiate into neurons, whereas progenitors at later stages, predominantly the SVZ intermediate progenitors, re-enter the cell cycle without differentiating, resulting in fewer upper-layer neurons 67 .…”

“…This appears to be the case for the zinc-finger transcription factor, Sal1, which is highly expressed in cortical progenitors but downregulated in differentiating neurons 67 . In Sal1 knockout mice, progenitors in the early stages of corticogenesis, predominantly the VZ radial glial cells, prematurely exit the cell cycle and differentiate into neurons, whereas progenitors at later stages, predominantly the SVZ intermediate progenitors, re-enter the cell cycle without differentiating, resulting in fewer upper-layer neurons 67 . Another regulator of progenitor cell cycle is Gde2, a six-transmembrane protein that is detected throughout corticogenesis in postmitotic neurons 68 .…”

STOP floxing around: Specificity and leakiness of inducible Cre/loxP systems

“…While Cx3cr1 CreER mice target CX3CR1 + cells including microglia and BAMs [5,17], the Sall1 CreER strain induces recombination in microglia while sparing BAMs [18]. Yet, outside of the immune compartment, Sall1 is also expressed by kidney mesenchymal cells and other CNS cells, predominantly in the embryonic pre‐neuroectoderm [19,20]. In the first article, Van Hove et al.…”

The Mendelian disorders of the epigenetic machinery

“…Hippocampal memory defects have been described in mouse models of Kabuki syndrome ), Kleefstra syndrome (Balemans et al 2014), Rubinstein-Taybi syndrome (Alarcón et al 2004;Korzus et al 2004), Sotos syndrome (Almuriekhi et al 2015), Weaver syndrome , and several other syndromes. Defects of many of the components of the epigenetic machinery also lead to neurogenesis defects in the granule cell layer of the dentate gyrus (Lopez-Atalaya et al 2011;Bjornsson et al 2014;Zhang et al 2014), defects of cortical neurogenesis (Harrison et al 2012;Ritchie et al 2014), and deficient synaptic plasticity (Levenson et al 2006;Sando et al 2012). This raises the question whether cells undergoing neurogenesis and synaptogenesis are particularly sensitive to subtle defects of the epigenetic machinery and downstream epigenetic abnormalities.…”