Bacterial TLR2/6 Ligands Block Ciliogenesis, Derepress Hedgehog Signaling, and Expand the Neocortex

Area of Science:

• Neuroscience
• Developmental Biology
• Immunology

Background:

• Maternal infections and microbial components can affect fetal brain development.
• Neural progenitor cells (NPCs) are critical for brain size and architecture.
• Mechanisms regulating NPCs are key to understanding brain developmental disorders.

Purpose of the Study:

• To identify cellular targets and molecular mechanisms of microbial components in the fetal brain.
• To investigate how bacterial cell wall (BCW) affects neural progenitor cells (NPCs).
• To elucidate the role of Toll-like receptors (TLRs) in mediating these effects.

Main Methods:

• Identified ventricular radial glia (vRG) as the primary NPC target of BCW.
• Investigated the interaction of BCW with Toll-like receptor 2 (TLR2) and Toll-like receptor 6 (TLR6).
• Assessed the impact of BCW-TLR2/6 interaction on ciliogenesis and Hedgehog (HH) signaling.

Main Results:

• BCW exposure shortened the cell cycle and increased self-renewal of vRGs, leading to increased neuronal output.
• BCW-TLR2 interaction suppressed ciliogenesis, derepressed Hedgehog signaling, and expanded vRGs.
• TLR6 was essential for BCW-mediated vRG expansion and also regulated cortical neuron number under normal conditions.

Conclusions:

• BCW acts on fetal neural progenitor cells via TLR2/6 and primary cilia, disrupting normal brain development.
• This interaction inhibits ciliogenesis, activates HH signaling, and leads to abnormal cortical architecture.
• TLR signaling plays a crucial role in regulating fetal brain development and neuronal cell number.