Local Apoptosis Modulates Early Mammalian Brain Development through the Elimination of Morphogen-Producing Cells

• Brain malformation in apoptosis-deficient mutants is not due to cell number increase
• Local apoptosis rapidly eliminates cluster of Fgf8-expressing cells at the ANR
• Apoptosis deficiency results in ANR accumulation of nonproliferative Fgf8+ cells
• Apoptosis shapes FGF8 morphogen distribution within limited developmental time window

SummaryApoptotic cells are observed in the early developing brain. Apoptosis deficiency is proposed to cause brain overgrowth, but here we show that brain malformations in apoptosis-deficient mutants are due to insufficient brain ventricle expansion as a result of uncompleted cranial neural tube closure. Apoptosis eliminates Fgf8-expressing cells in the anterior neural ridge (ANR), which acts as an organizing center of the forebrain by producing FGF8 morphogen. Deficiency of apoptosis leads to the accumulation of undead and nonproliferative cells in the ventral part of the ANR. The undead cells in apoptosis-deficient mutants express Fgf8 continuously, which perturbs gene expression in the ventral forebrain. Thus, apoptosis within a specific subdomain of the ANR is required for correct temporal elimination of an FGF8-producing region within a limited developmental time window, thereby ensuring proper forebrain development.

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