ABSTRACT
In recent years, much progress has been made in understanding the process by which the brain is organised into specific regions. Much less is known about the way neuronal subtypes are defined inside these areas and how the temporal control of connectivity between neurons is achieved. Our thought processes and behaviours depend upon the development of neuronal circuits located in the most anterior brain area: the telencephalon (forming our cerebral cortex). The transcription factor Foxg1 is crucial to the development of specific neuronal fates inside this region and recent findings in zebrafish and mouse unveiled its impact as an integrator of telencephalic signalling centres. This essential regulatory activity may be key to understand Foxg1-dependent human disorders.
Subject(s)
Forkhead Transcription Factors/metabolism , Prosencephalon/embryology , Prosencephalon/metabolism , Signal Transduction , Wnt Proteins/metabolism , Animals , Cell Lineage , Gene Expression Regulation, Developmental , Humans , Prosencephalon/cytologyABSTRACT
The forebrain is patterned along the dorsoventral (DV) axis by Sonic Hedgehog (Shh). However, previous studies have suggested the presence of an Shh-independent mechanism. Our study identifies Wnt/beta-catenin-activated from the telencephalic roof-as an Shh-independent pathway that is essential for telencephalic pallial (dorsal) specification during neurulation. We demonstrate that the transcription factor Foxg1 coordinates the activity of two signaling centers: Foxg1 is a key downstream effector of the Shh pathway during induction of subpallial (ventral) identity, and it inhibits Wnt/beta-catenin signaling through direct transcriptional repression of Wnt ligands. This inhibition restricts the dorsal Wnt signaling center to the roof plate and consequently limits pallial identities. Concomitantly to these roles, Foxg1 controls the formation of the compartment boundary between telencephalon and basal diencephalon. Altogether, these findings identify a key direct target of Foxg1, and uncover a simple molecular mechanism by which Foxg1 integrates two opposing signaling centers.
Subject(s)
Forkhead Transcription Factors/metabolism , Hedgehog Proteins/metabolism , Signal Transduction , Telencephalon/metabolism , Wnt Proteins/metabolism , Zebrafish Proteins/metabolism , Zebrafish/metabolism , Animals , Body Patterning/drug effects , Fishes , Gene Expression Regulation, Developmental/drug effects , Ligands , Mammals , Neural Tube/drug effects , Neural Tube/embryology , Oligonucleotides, Antisense/pharmacology , Promoter Regions, Genetic/genetics , Protein Binding/drug effects , Repressor Proteins/metabolism , Signal Transduction/drug effects , Telencephalon/cytology , Telencephalon/drug effects , Transcription, Genetic/drug effects , Up-Regulation/drug effects , Wnt Proteins/genetics , Zebrafish/embryology , beta Catenin/metabolismABSTRACT
The tumor suppressor Apc1 is an intracellular antagonist of the Wnt/beta-catenin pathway, which is vital for induction and patterning of the early vertebrate brain. However, its role in later brain development is less clear. Here, we examined the mechanisms underlying effects of an Apc1 zygotic-effect mutation on late brain development in zebrafish. Apc1 is required for maintenance of established brain subdivisions and control of local organizers such as the isthmic organizer (IsO). Caudal expansion of Fgf8 from IsO into the cerebellum is accompanied by hyperproliferation and abnormal cerebellar morphogenesis. Loss of apc1 results in reduced proliferation and apoptosis in the dorsal midbrain. Mosaic analysis shows that Apc is required cell-autonomously for maintenance of dorsal midbrain cell fate. The tectal phenotype occurs independently of Fgf8-mediated IsO function and is predominantly caused by stabilization of beta-catenin and subsequent hyperactivation of Wnt/beta-catenin signalling, which is mainly mediated through LEF1 activity. Chemical activation of the Wnt/beta-catenin in wild-type embryos during late brain maintenance stages phenocopies the IsO and tectal phenotypes of the apc mutants. These data demonstrate that Apc1-mediated restriction of Wnt/beta-catenin signalling is required for maintenance of local organizers and tectal integrity.
Subject(s)
Brain/embryology , Organizers, Embryonic/physiology , Tumor Suppressor Proteins/metabolism , Zebrafish Proteins/metabolism , Zebrafish/embryology , Animals , Body Patterning/physiology , Brain/abnormalities , Brain/metabolism , Embryo, Nonmammalian/metabolism , Fibroblast Growth Factors/metabolism , Mesencephalon/abnormalities , Mesencephalon/embryology , Mesencephalon/metabolism , Mutation , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Suppressor Proteins/genetics , Wnt Proteins/physiology , Zebrafish/metabolism , Zebrafish Proteins/genetics , beta Catenin/genetics , beta Catenin/metabolismABSTRACT
The tumor suppressor Apc1 is an intracellular antagonist of the Wnt/beta-catenin pathway. We examined the effects of an Apc1 loss-of-function mutation on retino-tectal axon pathfinding in zebrafish. In apc mutants, the retina is disorganized and optic nerves portray pathfinding defects at the optic chiasm and do not project properly to the tectum. Wild-type cells, transplanted into mutant retinae, acquire retinal ganglion cell fate and project axons that cross at the mispositioned optic chiasm and extend to the contralateral tectum, suggesting a function of apc1 in axon pathfinding. These defects are caused mainly by stabilization of beta-catenin. These data demonstrate that Apc1 function is required for correct patterning of the retina and proper retinal ganglion axon projections.
