Lef1-dependent hypothalamic neurogenesis inhibits anxiety

Area of Science:

• Neuroscience
• Developmental Biology
• Evolutionary Biology

Background:

• Innate behaviors are conserved across the animal kingdom.
• The developmental pathways for neuronal populations mediating innate behaviors are not fully understood.
• The role of signaling pathways in regulating these behaviors across diverse species remains unclear.

Purpose of the Study:

• To investigate if common signaling pathways regulate the development of neuronal populations mediating innate behaviors in diverse organisms.
• To determine the role of the Wnt/ß-catenin effector Lef1 in the differentiation of anxiolytic hypothalamic neurons.
• To explore the evolutionary conservation and divergence of Lef1-dependent pathways.

Main Methods:

• Comparative analysis of Lef1 function in zebrafish and mice.
• Identification of Lef1-dependent genes in neuroendocrine organs of zebrafish and Drosophila.
• Examination of ortholog gene expression in primate hypothalami (marmosets and humans).

Main Results:

• Lef1 is essential for anxiolytic hypothalamic neuron differentiation in both zebrafish and mice.
• The specific Lef1-dependent genes and neurons differ between zebrafish and mice.
• Zebrafish and Drosophila share common Lef1-dependent gene expression in neuroendocrine organs, indicating pathway conservation.
• Orthologs of Lef1-dependent genes show correlated hypothalamic expression in primates, suggesting parallel anxiolytic pathways.

Conclusions:

• The transcription factor Lef1 plays a conserved role in regulating anxiety across diverse species.
• Evolution has led to divergence in Lef1-dependent mechanisms for anxiety regulation, particularly in mammals.
• Lef1 regulates circuit development critical for mediating anxiety, highlighting its fundamental importance in animal behavior.