The facial neural crest controls fore- and midbrain patterning by regulating Foxg1 expression through Smad1 activity

Abstract

The facial neural crest (FNC), a pluripotent embryonic structure forming craniofacial structures, controls the activity of brain organisers and stimulates cerebrum growth. To understand how the FNC conveys its trophic effect, we have studied the role of Smad1, which encodes an intracellular transducer, to which multiple signalling pathways converge, in the regulation of Foxg1. Foxg1 is a transcription factor essential for telencephalic specification, the mutation of which leads to microcephaly and mental retardation. Smad1 silencing, based on RNA interference (RNAi), was performed in pre-migratory FNC cells. Soon after electroporation of RNAi molecules, Smad1 inactivation abolished the expression of Foxg1 in the chick telencephalon, resulting in dramatic microcephaly and partial holoprosencephaly. In addition, the depletion of Foxg1 activity altered the expression Otx2 and Foxa2 in di/ mesencephalic neuroepithelium. However, when mutated forms of Smad1 mediating Fgf and Wnt signalling were transfected into FNC cells, these defects were overcome. We also show that, downstream of Smad1 activity, Dkk1, a Wnt antagonist produced by the FNC, initiated the specification of the telencephalon by regulating Foxg1 activity. Additionally, the activity of Cerberus in FNC-derived mesenchyme synergised with Dkk1 to control Foxg1 expression and maintain the balance between Otx2 and Foxa2.

Evolution of vertebrates as viewed from the crest

“…At a molecular level, this results from production of BMP inhibitors, Gremlin and Noggin, by the rostral neural crest that in turn lead to regulation of expression of FGF8 in the anterior neural ridge (ANR). Consistent with this, implantation of FGF8 beads after neural crest ablation rescues this phenotype to restore subsequent downstream signaling events and proper head development 101,114 . FGF signaling associated with an ANR-like signaling center is potentially present throughout deuterostomes 115,116 , suggesting that that neural crest cells have adopted or coopted roles in regulation of neural/craniofacial patterning, at least in amniotes.…”

Neural retina identity is specified by lens‐derived BMP signals

“…8). In agreement with this, a recent study in chick has provided evidence that a reduction in Noggin and Gremlin expression in the cephalic neural crest cells results in abolished FoxG1 expression in the telencephalon and subsequent microcephaly and partial holoprosencephaly (Aguiar et al, 2014). Our results, showing that BMP signals inhibit telencephalic identity while promoting neural retina character, highlight a new role for BMP signals during the development of the retina that is distinct from previously described roles in dorso-ventral patterning of the retina (Adler and BeleckyAdams, 2002;Kobayashi et al, 2010;Murali et al, 2005) and fate choice between neural versus RPE cells (Hyer et al, 2003;Muller et al, 2007).…”

Evolutionary conservation and conversion of Foxg1 function in brain development

“…The establishment of the Foxg1-expressing telencephalic compartment is also mediated through interactions between multiple signaling molecules that are expressed across the telencephalic-diencephalic territory, in which Smad1 acts as signaling transducer of Fgf8 to regulate downstream DKK1 and Gremlin/Noggin, Cerberus expression. This signaling cascade further secures the rostral Foxg1 expression in the anterior territory (Aguiar et al 2014) (Fig. 2, top panel).…”

“…This signaling cascade further secures the rostral Foxg1 expression in the anterior territory (Aguiar et al . ) (Fig. , top panel).…”