Lhx1 Controls Terminal Differentiation and Circadian Function of the Suprachiasmatic Nucleus

Bedont, Joseph L.; LeGates, Tara A.; Slat, Emily A.; Byerly, Mardi S.; Wang, Hong; Hu, Jianfei; Rupp, Alan C.; Qian, Jiang; Wong, G. William; Herzog, Erik D.; Hattar, Samer; Blackshaw, Seth

doi:10.1016/j.celrep.2014.03.060

Cited by 88 publications

(139 citation statements)

References 65 publications

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“…In addition, we found that expression of Lhx1 is higher in supraclavicular mature adipocytes, while expression of Bglap2 is higher in supraclavicular preadipocytes. This suggests that Lhx1, a transcription factor involved in tissue development (39)(40)(41), and Bglap2, a hormone secreted from the bone that can regulate insulin sensitivity (42), may have unique roles in the regulation of scBAT function. Further research is warranted to determine the roles of these newly identified scBAT-specific genes.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of a supraclavicular brown adipose tissue in mice

Mo¹,

Salley

Roshan

et al. 2017

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Identification and characterization of a supraclavicular brown adipose tissue in mice

Mo¹,

Salley

Roshan

et al. 2017

JCI Insight

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“…The increase in synchrony in the SCN at E15.5 does coincide with Lhx1 expression across the SCN (VanDunk et al, 2011). This transcription factor is important for the expression of diverse neuropeptide coupling signals aside from VIP, such as GRP or AVP (Bedont et al, 2014). Because these signals can mediate the synchrony in adults (Brown et al, 2005;Maywood 14 et al, 2011) and in postnatal ages (Ono et al, 2016), they are candidates for mediating SCN synchrony in embryonic development.…”

Section: Discussionmentioning

confidence: 99%

“…Transcription factors such as Lhx1, Shh, Six3, and Six6 participate in the embryonic specification of SCN lineages (Shimogori et al, 2010;VanDunk et al, 2011;Clark et al, 2013;Bedont et al, 2014). However, the markers of terminal differentiation and synaptogenesis peak postnatally (Moore and Bernstein, 1989;Shimogori et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Ontogeny of Circadian Rhythms and Synchrony in the Suprachiasmatic Nucleus

et al. 2017

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In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus coordinates daily rhythms including sleep-wake, hormone release and gene expression. The cells of the SCN must synchronize to each other to drive these circadian rhythms in the rest of the body. The ontogeny of circadian cycling and intercellular coupling in the SCN remains poorly understood. Recent in vitro studies have recorded circadian rhythms from the whole embryonic SCN. Here, we tracked the onset and precision of rhythms in PERIOD2 (PER2), a clock protein, within the SCN isolated from embryonic and postnatal mice of undetermined sex. We found that a few SCN cells developed circadian periodicity in PER2 by 14.5 days after mating (E14.5) with no evidence for daily cycling on E13.5. On E15.5, the fraction of competent oscillators increased dramatically corresponding with stabilization of their circadian periods. The cells of the SCN harvested at E15.5 expressed sustained, synchronous daily rhythms. By postnatal day 2 (P2), SCN oscillators displayed the daily, dorsal-ventral phase wave in clock gene expression typical of the adult SCN.Strikingly, vasoactive intestinal polypeptide (VIP), a neuropeptide critical for synchrony in the adult SCN, and its receptor, VPAC2R, reached detectable levels after birth and after the onset of circadian synchrony. Antagonists of GABA or VIP signaling or action potentials did not disrupt circadian synchrony in the E15.5 SCN. We conclude that endogenous daily rhythms in the fetal SCN begin with few noisy oscillators on E14.5, followed by widespread oscillations that rapidly synchronize on E15.5 by an unknown mechanism. 2 Significance StatementWe recorded the onset of PER2 circadian oscillations during embryonic development in the mouse SCN. When isolated at E13.5, the anlagen of the SCN expresses high, arrhythmic PER2. In contrast, a few cells show noisy circadian rhythms in the isolated E14.5 SCN and most show reliable, self-sustained, synchronized rhythms in the E15.5 SCN. Strikingly, this synchrony at E15.5 appears prior to expression of VIP or its receptor and persists in the presence of blockers of VIP, GABA or neuronal firing. Finally, the dorsal-ventral phase wave of PER2 typical of the adult SCN appears around P2, indicating that multiple signals may mediate circadian synchrony during the ontogeny of the SCN.

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“…The ZFHX3/ATaxis therefore bridges across cell-autonomous and circuit-level circadian functions (Parsons et al 2015). Other developmentally relevant transcription factors are also known to regulate specific neuropeptidergic expression in the SCN, suggesting that the motif of combined cell-autonomous and circuit-level activity seen in ZFHX3 may be more prevalent (Bedont et al 2014). In the particular case of ZFHX3, the effects on period of heterozygotes deletion and in vivo knockdown occur after maturation of the SCN and therefore are independent of any developmental role regulated by this transcription factor.…”

Section: Role Of Zfhx3: Bridging Cells and Circuitsmentioning

confidence: 99%

Regulating the Suprachiasmatic Nucleus (SCN) Circadian Clockwork: Interplay between Cell-Autonomous and Circuit-Level Mechanisms

Herzog

Hermanstyne

Smyllie

et al. 2017

Cold Spring Harb Perspect Biol

185

171

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The suprachiasmatic nucleus (SCN) is the principal circadian clock of the brain, directing daily cycles of behavior and physiology. SCN neurons contain a cell-autonomous transcription-based clockwork but, in turn, circuit-level interactions synchronize the 20,000 or so SCN neurons into a robust and coherent daily timer. Synchronization requires neuropeptide signaling, regulated by a reciprocal interdependence between the molecular clockwork and rhythmic electrical activity, which in turn depends on a daytime Na þ drive and nighttime K þ drag. Recent studies exploiting intersectional genetics have started to identify the pacemaking roles of particular neuronal groups in the SCN. They support the idea that timekeeping involves nonlinear and hierarchical computations that create and incorporate timing information through the interactions between key groups of neurons within the SCN circuit. The field is now poised to elucidate these computations, their underlying cellular mechanisms, and how the SCN clock interacts with subordinate circadian clocks across the brain to determine the timing and efficiency of the sleep -wake cycle, and how perturbations of this coherence contribute to neurological and psychiatric illness.W e wake and sleep each day. Hormones reach peak plasma levels at specified times, for example cortisol peaks in the early morning. These, and many other physiological and behavioral, daily rhythms depend on an internal circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus. Prior reviews have provided excellent summaries of research progress in the location and function of this body clock (Weaver 1998). This work focuses on recent advances in our understanding of the genetic basis for cell-autonomous generation of circadian time, and how cells within the SCN synchronize their daily rhythms across the circuit to produce a coherent oscillation in neuronal activity. It is these circuit-level emergent properties of the SCN that ultimately direct daily behaviors such as wake and sleep.

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Lhx1 Controls Terminal Differentiation and Circadian Function of the Suprachiasmatic Nucleus

Cited by 88 publications

References 65 publications

Identification and characterization of a supraclavicular brown adipose tissue in mice

Identification and characterization of a supraclavicular brown adipose tissue in mice

Ontogeny of Circadian Rhythms and Synchrony in the Suprachiasmatic Nucleus

Regulating the Suprachiasmatic Nucleus (SCN) Circadian Clockwork: Interplay between Cell-Autonomous and Circuit-Level Mechanisms

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