2 research outputs found
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 Lhx1âs control of Vip expression. Others, such as the
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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