Foxg1 Directly Represses Dbx1 to Confine the POA and Subsequently Regulate Ventral Telencephalic Patterning

Abstract

During early development, signaling centers, such as the cortical hem and the preoptic area (POA), are critical for telencephalic patterning. However, the mechanisms underlying the maintenance of signal centers are poorly understood. Here, we report that the transcription factor Foxg1 is required to confine the POA, a resource of Sonic Hedgehog (Shh) that is pivotal for ventral telencephalic development. Cell-specific deletion of Foxg1 achieved by crossing Foxg1fl/fl with Dbx1-cre or Nestin-CreER combined with tamoxifen induction results in a dramatic expansion of the POA accompanied by the significantly increased activity of the Shh signaling pathway. Ventral pattern formation was severely impaired. Moreover, we demonstrated that Foxg1 directly represses Dbx1 to restrict the POA. Furthermore, we found that the ventral pallium was expanded, which might also contribute to the observed patterning defects. These findings will improve our understanding of the maintenance of signal centers and help to elucidate the mechanisms underlying ventral telencephalic patterning.

Fetal neural progenitors process TLR signals from bacterial components to enhance proliferation and rework brain development

“…FOXG1 is a nuclear transcriptional repressor expressed very early in development and promotes expansion of NPCs (Seoane et al, 2004;Xuan et al, 1995;Hanashima et al, 2004;Hanashima et al, 2002;Miyoshi and Fishell, 2012;Martynoga et al, 2005;Regad et al, 2007;Shen et al, 2006;Du et al, 2019). In humans, altered levels of FOXG1 is associated with a high risk of abnormal behavior and autism (Hazlett et al, 2017;al Haddad et al, 2019;Scharfman and Hen, 2007;Wong et al, 2019), a phenotype recapitulated in our mouse model.…”

A forebrain undivided: Unleashing model organisms to solve the mysteries of holoprosencephaly

“…Six3, in turn, directly activates transcription of Shh, thus establishing a positive feedback loop . Six3 also activates transcription of FoxG1, a forkhead transcription factor that is essential for telencephalic development across vertebrates . The dorsal midline produces two classes of secreted growth factors, BMPs and Wnts.…”

“…In mammals, Gli2 activates transcription of a homeobox transcription factor Six3, which in turn activates transcription of Shh, thus establishing a positive feedback loop . Six3 also activates transcription of FoxG1, a forkhead transcription factor that is essential for telencephalic development across vertebrates . While mutations in human FOXG1 have not been linked to HPE, they are associated with a spectrum of neurodevelopmental anomalies that include microcephaly, developmental delay and seizure disorders .…”

“…23,30 Six3 also activates transcription of FoxG1, a forkhead transcription factor that is essential for telencephalic development across vertebrates. [31][32][33][34][35] The dorsal midline produces two classes of secreted growth factors, BMPs and Wnts. Wnts induce telencephalic expression of Zic2, which in turn represses transcription Six3.…”

Disruption of Foxg1 impairs neural plasticity leading to social and cognitive behavioral defects

“…Foxg1, a member of the Forkhead box transcription factor family, has been reported to be critical for telencephalon development [8]. Early disruption of Foxg1 results in severe defects in pattern formation, cell proliferation, cell fate determination and neuronal migration [9][10][11][12][13][14][15][16]. Mutations in Foxg1 cause a severe neurodevelopmental disorder known as FOXG1 syndrome (former cognition variant of Rett syndrome) [17].…”