Gli3 Controls Corpus Callosum Formation by Positioning Midline Guideposts During Telencephalic Patterning

The corpus callosum (CC) represents the major forebrain commissure connecting the 2 cerebral hemispheres. Midline crossing of callosal axons is controlled by several glial and neuronal guideposts specifically located along the callosal path, but it remains unknown how these cells acquire their position. Here, we show that the Gli3 hypomorphic mouse mutant Polydactyly Nagoya (Pdn) displays agenesis of the CC and mislocation of the glial and neuronal guidepost cells. Using transplantation experiments, we demonstrate that agenesis of the CC is primarily caused by midline defects. These defects originate during telencephalic patterning and involve an up-regulation of Slit2 expression and altered Fgf and Wnt/β-catenin signaling. Mutations in sprouty1/2 which mimic the changes in these signaling pathways cause a disorganization of midline guideposts and CC agenesis. Moreover, a partial recovery of midline abnormalities in Pdn/Pdn;Slit2−/− embryos mutants confirms the functional importance of correct Slit2 expression levels for callosal development. Hence, Gli3 controlled restriction of Fgf and Wnt/β-catenin signaling and of Slit2 expression is crucial for positioning midline guideposts and callosal developmen

Gli3 Controls Corpus Callosum Formation by Positioning Midline Guideposts During Telencephalic Patterning

The corpus callosum (CC) represents the major forebrain commissure connecting the 2 cerebral hemispheres. Midline crossing of callosal axons is controlled by several glial and neuronal guideposts specifically located along the callosal path, but it remains unknown how these cells acquire their position. Here, we show that the Gli3 hypomorphic mouse mutant Polydactyly Nagoya (Pdn) displays agenesis of the CC and mislocation of the glial and neuronal guidepost cells. Using transplantation experiments, we demonstrate that agenesis of the CC is primarily caused by midline defects. These defects originate during telencephalic patterning and involve an up-regulation of Slit2 expression and altered Fgf and Wnt/β-catenin signaling. Mutations in sprouty1/2 which mimic the changes in these signaling pathways cause a disorganization of midline guideposts and CC agenesis. Moreover, a partial recovery of midline abnormalities in Pdn/Pdn;Slit2(-/-) embryos mutants confirms the functional importance of correct Slit2 expression levels for callosal development. Hence, Gli3 controlled restriction of Fgf and Wnt/β-catenin signaling and of Slit2 expression is crucial for positioning midline guideposts and callosal development

Timing of complementary feeding for early childhood allergy prevention: An overview of systematic reviews.

OBJECTIVE: To summarise and critically appraise systematic review (SR) evidence on the effects of timing of complementary feeding (CF) on the occurrence of allergic sensitisation and disease. DESIGN: Overview of SRs. AMSTAR-2 and ROBIS were used to assess methodological quality and risk of bias (RoB) of SRs. RoB 2 Tool was used to assess RoB of primary randomised controlled trials (RCTs) (or extracted). The certainty of evidence (CoE) was assessed using GRADE. Findings were synthesised narratively. DATA SOURCES: MEDLINE (via PubMed and Ovid), the Cochrane Library and Web of Science Core Collection (2010 to 27 February 2023). ELIGIBILITY CRITERIA: SRs investigating the effects of timing of CF in infants or young children (0-3 years) on risk of developing food allergy (FA), allergic sensitisation, asthma, allergic rhinitis, atopic eczema and adverse events based on RCT evidence. RESULTS: Eleven SRs were included. Only two SRs had low RoB; common issues were failure to report on funding of primary studies and failure to provide a list of excluded trials. Common limitations of included trials were lack of blinding of outcome assessment or detailed trial preregistration, and inadequate handling of high loss to follow up. Primary study overlap was very high for specific FA and slight to moderate for FA in general and other primary outcomes. Introducing specific foods (peanut, cooked egg) early probably reduces the risk of specific FA. Evidence for other allergic outcomes was mostly very uncertain and based on few primary studies. Trials varied regarding timing of CF, nature of complementary foods and population risk, which limited comparability between SRs. CONCLUSIONS: For developing guidelines to support decision-making on the timing of CF as a preventive strategy, early introduction of specific foods (i.e. egg and peanut) seems promising and safe, whereas more extensive research is required regarding other allergic outcomes and potential adverse events

A Crucial Role for Primary Cilia in Cortical Morphogenesis

Primary cilia are important sites of signal transduction involved in a wide range of developmental and postnatal functions. Proteolytic processing of the transcription factor Gli3, for example, occurs in primary cilia, and defects in intraflagellar transport (IFT), which is crucial for the maintenance of primary cilia, can lead to severe developmental defects and diseases. Here we report an essential role of primary cilia in forebrain development. Uncovered by N-ethyl-N-nitrosourea-mutagenesis, cobblestone is a hypomorphic allele of the IFT gene Ift88, in which Ift88 mRNA and protein levels are reduced by 70-80%. cobblestone mutants are distinguished by subpial heterotopias in the forebrain. Mutants show both severe defects in the formation of dorsomedial telencephalic structures, such as the choroid plexus, cortical hem and hippocampus, and also a relaxation of both dorsal-ventral and rostral-caudal compartmental boundaries. These defects phenocopy many of the abnormalities seen in the Gli3 mutant forebrain, and we show that Gli3 proteolytic processing is reduced, leading to an accumulation of the full-length activator isoform. In addition, we observe an upregulation of canonical Wnt signaling in the neocortex and in the caudal forebrain. Interestingly, the ultrastructure and morphology of ventricular cilia in the cobblestone mutants remains intact. Together, these results indicate a critical role for ciliary function in the developing forebrain