Expression of the bHLH transcription factor Tcf12 (ME1) gene is linked to the expansion of precursor cell populations during neurogenesis

Abstract

In this study, we focused on the potential function of the murine gene Tcf12 (also known as ME1 or HEB) encoding the bHLH E-protein ME1 during brain development. An exencephaly phenotype of low penetrance has consistently been observed in both Tcf12 null mice and Tcf12(dm) homozygous mice. Thus, to address the possible underlying mechanism of the Tcf12 gene during the early steps of brain development, we performed a detailed analysis of its spatio-temporal expression pattern at distinct steps of gastrulation and neurogenesis. We found that Tcf12 transcripts are detected in the embryonic ectoderm prior to neural induction during gastrulation. During neurulation, Tcf12 transcripts are evident at high levels in the proliferating neuroepithelium of the neural folds and the cephalic mesenchyme. Thus, Tcf12 gene expression coincides with the massive proliferation occurring in the forming neuroepithelium and cephalic mesenchyme during neural tube formation, which is consistent with the exencephaly phenotype of Tcf12 null mice. In the developing cortex and spinal cord, Tcf12 expression is restricted to the proliferative ventricular zones, indicating that Tcf12 expression is down regulated when these neuronal cells undergo their final differentiation. Interestingly, we found that the postnatal Tcf12 expression parallels the ongoing adult neurogenesis in the mitotically active subventricular zone. Thus, the timing and location of Tcf12 expression combined with this severe neurulation defect support our hypothesis that the Tcf12 gene may be involved in the control of proliferating neural stem cells and progenitor cells and that it may be critical to sustain their undifferentiated state during embryonic and adult neurogenesis.

An RNA-binding protein, Qki5, regulates embryonic neural stem cells through pre-mRNA processing in cell adhesion signaling

“…In addition, we confirmed three models of the Qki5-binding position-dependent alternative splicing in neural stem cells using a series of representative validations, including Tcf12 (a neural stem cell transcription factor gene), in which Qki5-dependent exon skipping occurred; Evl, a gene encoding an actin-binding protein; and spag9, a gene encoding a member of the cancer testis antigen gene family in which Qki5-dependent exon inclusion occurred (Shankar et al 1998;Uittenbogaard and Chiaramello 2002;Michael et al 2010;Pollen et al 2015). For these genes, Qki5-dependent exon inclusion and skipping were observed as well as both the Qki5-binding code and CLIP clusters close to the alternative exon along the present splicing rule (Fig.…”

The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors

“…Because their bHLH domains are highly homologous, it has been proposed that E-proteins have redundant functions, despite obvious phenotypes in animals lacking any one of them (18,19). Although all E-proteins are highly expressed in neural progenitors (20,21), their role in nervous system development has not been investigated in depth (22). Recently, genetic studies demonstrated that loss of one copy of TCF4 causes Pitt-Hopkins syndrome (PHS) (23)(24)(25), a neurodevelopmental disease characterized by mental retardation, seizures, and hyperventilation (26,27), suggesting that TCF4 is critical for human nervous system development.…”

Gene Expression Changes in the Course of Neural Progenitor Cell Differentiation

“…In addition, some of our identified genes have been reported previously to be expressed within neural germinal zones. These are Tenascin C (Jankovski and Sotelo, 1996), Hb-Egf (Nakagawa et al, 1998), Nell2 (Kim et al, 2002), Transcription factor 12 (Uittenbogaard and Chiaramello, 2002), Cyclin D1, Cyclin D2 (Geschwind et al, 2001), andLrrfip1, Hmg2b, Racgap1, Olig2, Fabp7, andPttg1 (Karsten et al, 2003).…”