Six1 is essential for early neurogenesis in the development of olfactory epithelium

Abstract

The olfactory epithelium (OE) is derived from the olfactory placode (OP) during mouse development. At embryonic day (E) 10.0-E10.5, "early neurogenesis" occurs in the OE, which includes production of pioneer neurons that emigrate out of the OE and other early-differentiated neurons. Around E12.5, the OE becomes organized into mature pseudostratified epithelium and shows "established neurogenesis," in which olfactory receptor neurons (ORNs) are differentiated from basal progenitors. Little is known about the molecular pathway of early neurogenesis. The homeodomain protein Six1 is expressed in all OP cells and neurogenic precursors in the OE. Here we show that early neurogenesis is severely disturbed despite the unaltered expression of Mash1 at E10.5 in the Six1-deficient mice (Six1-/-). Expression levels of neurogenin1 (Ngn1) and NeuroD are reduced and those of Hes1 and Hes5 are augmented in the OE of Six1-/- at E10.5. Pioneer neurons and cellular aggregates, which are derived from the OP/OE and situated in the mesenchyme between the OE and forebrain, are completely absent in Six1-/-. Moreover, ORN axons and the gonadotropin-releasing hormone-positive neurons fail to extend and migrate to the forebrain, respectively. Our study indicates that Six1 plays critical roles in early neurogenesis by regulating Ngn1, NeuroD, Hes1, and Hes5.

MicroRNA-30a regulates zebrafish myogenesis via targeting the transcription factor Six1

“…In the inner ear, six1b has divergent roles, as it promotes hair cell fate but inhibits neuronal fate (Bricaud and Collazo, 2011). Additional tissues in which SIX1 plays an important embryonic role have been identified in several species, including several embryonic placodes and the kidney, amongst others (Brugmann et al, 2004;Grifone et al, 2005;Ikeda et al, 2007;Laclef et al, 2003b;Sato et al, 2010). Similar to what is observed in myogenesis, many of these tissues require SIX1 early during development to promote cell survival, proliferation and migration, but SIX1 protein expression soon decreases later in embryogenesis and is mostly absent in mature tissues (Christensen et al, 2008).…”

Six1 expression is associated with a poor prognosis in patients with glioma

“…The Six1 homeoprotein is a member of the Six family of homeodomain transcription factors and has been found to be upregulated in multiple cancers, including breast cancer (12,20,24), rhabdomyosarcomas (18,25,26), hepatocellular carcinomas (19), ovarian cancer (13) and Wilms' tumors (17). In addition, Six1 plays a role in cellular migration and invasion during embryogenesis (22,(27)(28)(29)(30) and in breast cancer (31,32). Notably, a recent study demonstrated that messenger RNA profiling of Six1 is dysregulated in A2B5 + glioma tumor progenitor cells from A2B5 + glial progenitor cells isolated from normal white matter (33).…”

Six1 is indispensable for production of functional progenitor cells during olfactory epithelial development

“…Before the established neurogenesis, the olfactory placode (OP)/OE contains thickened olfactory neuroepithelial cells and their cell bodies expand from the apical to the basal side. "Early neurogenesis" or "primary neurogenesis" commences at E10.0 and some cells become neurons in a scattered pattern in the OP/OE (Ikeda et al, 2007). Early neurogenesis gives rise to at least two distinct classes of neurons.…”

“…Pioneer neurons form "cellular aggregates" at later developmental stage (Schwanzel-Fukuda et al, 1992), which are required for axonal projection of later-born ORNs and for migration of gonadotropin-releasing hormone (GnRH) neurons (Schwanzel-Fukuda et al, 1992;Ikeda et al, 2007). The other class is the early-differentiated neurons whose characteristic and cell fate are currently unknown (Ikeda et al, 2007).…”

“…Six1 encodes a transcription factor and plays critical roles in the development of sensory organs (Zheng et al, 2003;Ozaki et al, 2004;Ikeda et al, 2007;Chen et al, 2009). We reported previously that Six1 is expressed in the OP and developing OE of mouse.…”