The Role of Lim Homeodomain Transcription Factor 1 in Suprachiasmatic Nucleus Development and Circadian Function

The suprachiasmatic nucleus (SCN) is the central light-entrained oscillator in mammals, transducing luminance input from the environment into holistic organism-wide coordination of cellular clocks on the solar time-scale. Yet despite this critical role, SCN development was poorly understood; at the beginning of my thesis, not a single transcription factor directly involved in its specification or differentiation was known. During my tenure, work from several labs has begun the long process of dissecting the transcriptional network controlling this process, including my thesis work on Lim homeodomain transcription factor 1 (Lhx1). Lhx1 is essential for terminal differentiation of several cell populations in the developing SCN, with an especially important role in promoting the expression of key SCN-enriched genes involved in signal transduction, including neuropeptide transmitters and their receptors and second messengers. Furthermore, through Vip signaling, Lhx1 indirectly controls the expression of numerous other SCN-enriched genes, including additional neuropeptides, among other actors. These transcriptional relationships give rise to a number of circadian phenotypes in Six3- Cre;Lhx1lox/lox mutants that lack Lhx1 in the developing SCN. Some phenotypes, like reduced synchronization of local cellular clocks in the SCN and wheel-running behavior, appear to be a result primarily of Lhx1’s control of Vip expression. Others, such as the iii near flattening of sleep rhythms and susceptibility to temperature entrainment by fever, appear to be critically reliant on Lhx1-controlled but Vip-independent gene expression lost in our mutants. In the process of investigating these questions, my collaborators and I have also gained novel and valuable insights into adult SCN physiology, which include the first in vivo cannulation data demonstrating previously unknown synergies among SCN neuropeptide signals, as well as the first direct in vivo evidence supporting a role for the SCN in the robustness of behavioral rhythms in the face of thermal insults. It is our hope that these findings, among others, clearly communicate the value of approaching adult circadian physiology from a developmental perspective