Lhx1 Controls Terminal Differentiation and Circadian Function of the Suprachiasmatic Nucleus

• Lhx1 is required for expression of SCN-enriched neuropeptides
• Molecular rhythms of normal period but reduced amplitude persist in Lhx1-deficient SCN
• Activity rhythms of Lhx1 mutants are severely disorganized in constant darkness
• Lhx1 mutants are hypersensitive to neuropeptide-induced changes in phase and period

SummaryVertebrate circadian rhythms are organized by the hypothalamic suprachiasmatic nucleus (SCN). Despite its physiological importance, SCN development is poorly understood. Here, we show that Lim homeodomain transcription factor 1 (Lhx1) is essential for terminal differentiation and function of the SCN. Deletion of Lhx1 in the developing SCN results in loss of SCN-enriched neuropeptides involved in synchronization and coupling to downstream oscillators, among other aspects of circadian function. Intact, albeit damped, clock gene expression rhythms persist in Lhx1-deficient SCN; however, circadian activity rhythms are highly disorganized and susceptible to surprising changes in period, phase, and consolidation following neuropeptide infusion. Our results identify a factor required for SCN terminal differentiation. In addition, our in vivo study of combinatorial SCN neuropeptide disruption uncovered synergies among SCN-enriched neuropeptides in regulating normal circadian function. These animals provide a platform for studying the central oscillator’s role in physiology and cognition.

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