Circadian Function in Multiple Cell Types Is Necessary for Proper Timing of the Preovulatory LH Surge

2019 ◽  
Vol 34 (6) ◽  
pp. 622-633 ◽  
Author(s):  
Eric L. Bittman
Keyword(s):  
Cell Types ◽  
Noticeable Effect ◽  
Lh Surge ◽  
Conditional Deletion ◽  
Proper Timing ◽  
Circadian Control ◽  
Gnrh Neurons ◽  
Multiple Cell ◽  
Locomotor Rhythms ◽  
Lh Secretion

The timing of the preovulatory surge of luteinizing hormone (LH), which occurs on the evening of proestrus in female mice, is determined by the circadian system. The identity of cells that control the phase of the LH surge is unclear: evidence supports a role of arginine vasopressin (AVP) cells of the suprachiasmatic nucleus (SCN), but it is not known whether vasopressinergic neurons are necessary or sufficient to account for circadian control of ovulation. Among other cell types, evidence also suggests important roles of circadian function of kisspeptin cells of the anteroventral periventricular nucleus (AvPV) and gonadotropin-releasing hormone (GnRH) neurons of the preoptic area (POA), whose discharge is immediately responsible for the discharge of LH from the anterior pituitary. The present studies used an ovariectomized, estradiol-treated preparation to determine critical cell types whose clock function is critical to the timing of LH secretion. As expected, the LH surge occurred at or shortly after ZT12 in control mice. In further confirmation of circadian control, the surge was advanced by 2 h in tau mutant animals. The timing of the surge was altered to varying degrees by conditional deletion of Bmal1 in AVPCre, KissCreBAC, and GnRHCreBAC mice. Excision of the mutant Cnsk1e (tau) allele in AVP neurons resulted in a reversion of the surge to the ZT12. Conditional deletion of Bmal1 in Kiss1 or GnRH neurons had no noticeable effect on locomotor rhythms, but targeting of AVP neurons produced variable effects on circadian period that did not always correspond to changes in the phase of LH secretion. The results indicate that circadian function in multiple cell types is necessary for proper timing of the LH surge.

scholarly journals MyD88 Is Not Required for Muscle Injury-Induced Endochondral Heterotopic Ossification in a Mouse Model of Fibrodysplasia Ossificans Progressiva

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 630
Author(s):  
Huili Lyu ◽  
Cody M. Elkins ◽  
Jessica L. Pierce ◽  
C. Henrique Serezani ◽  
Daniel S. Perrien
Keyword(s):  
Heterotopic Ossification ◽  
Muscle Injury ◽  
Cell Types ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Inflammatory Signaling ◽  
Conditional Deletion ◽  
Pathway Crosstalk ◽  
Multiple Cell

Excess inflammation and canonical BMP receptor (BMPR) signaling are coinciding hallmarks of the early stages of injury-induced endochondral heterotopic ossification (EHO), especially in the rare genetic disease fibrodysplasia ossificans progressiva (FOP). Multiple inflammatory signaling pathways can synergistically enhance BMP-induced Smad1/5/8 activity in multiple cell types, suggesting the importance of pathway crosstalk in EHO and FOP. Toll-like receptors (TLRs) and IL-1 receptors mediate many of the earliest injury-induced inflammatory signals largely via MyD88-dependent pathways. Thus, the hypothesis that MyD88-dependent signaling is required for EHO was tested in vitro and in vivo using global or Pdgfrα-conditional deletion of MyD88 in FOP mice. As expected, IL-1β or LPS synergistically increased Activin A (ActA)-induced phosphorylation of Smad 1/5 in fibroadipoprogenitors (FAPs) expressing Alk2R206H. However, conditional deletion of MyD88 in Pdgfrα-positive cells of FOP mice did not significantly alter the amount of muscle injury-induced EHO. Even more surprisingly, injury-induced EHO was not significantly affected by global deletion of MyD88. These studies demonstrate that MyD88-dependent signaling is dispensable for injury-induced EHO in FOP mice.

scholarly journals Pup removal suppresses estrogen-induced surges of LH secretion and activation of GnRH neurons in lactating rats

2006 ◽  
Vol 191 (1) ◽  
pp. 339-348 ◽  
Author(s):  
Atsushi Fukushima ◽  
Ping Yin ◽  
Maho Ishida ◽  
Nobuhiro Sugiyama ◽  
Jun Arita
Keyword(s):  
Third Ventricle ◽  
Acute Effect ◽  
Suppressive Effect ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Indwelling Catheter ◽  
Lh Surge ◽  
Gnrh Neurons ◽  
Double Immunohistochemical Staining ◽  
Lh Secretion

During lactation, the suckling stimulus exerts profound influences on neuroendocrine regulation in nursing rats. We examined the acute effect of pup removal on the estrogen-induced surge of LH secretion in ovariectomized lactating rats. Lactating and nonlactating cyclic female rats were given an estradiol-containing capsule after ovariectomy, and blood samples were collected through an indwelling catheter for serum LH determinations. In lactating, freely suckled ovariectomized rats, estrogen treatment induced an afternoon LH surge with a magnitude and timing comparable to those seen in nonlactating rats. Removal of pups from the lactating rats at 0900, 1100, or 1300 h, but not at 1500 h, suppressed the estrogen-induced surge that normally occurs in the afternoon of the same day. The suppressive effect of pup removal at 0900 h was completely abolished when the pups were returned by 1400 h. In contrast, pup removal was ineffective in abolishing the stimulatory effect of progesterone on LH surges. Double immunohistochemical staining for gonadotropin-releasing hormone (GnRH) and c-Fos, a marker for neuronal activation, revealed a decrease, concomitantly with the suppression of LH surges, in the number of c-Fos-immunoreactive GnRH neurons in the preoptic regions of nonsuckled rats. An LH surge was restored in nonsuckled rats when 0.1 μg oxytocin was injected into the third ventricle three times at 1-h intervals during pup removal. These results suggest that the GnRH surge generator of lactating rats requires the suckling stimulus that is not involved in nonlactating cyclic female rats.

scholarly journals Interactions between neurotensin and GnRH neurons in the positive feedback control of GnRH/LH secretion in the mouse

2010 ◽  
Vol 298 (1) ◽  
pp. E80-E88 ◽  
Author(s):  
Heather M. Dungan Lemko ◽  
Roxana Naderi ◽  
Valeriya Adjan ◽  
Lothar H. Jennes ◽  
Victor M. Navarro ◽  
...  
Keyword(s):  
Basal Forebrain ◽  
Neural Circuits ◽  
Direct Role ◽  
Lh Surge ◽  
Periventricular Nucleus ◽  
Gnrh Neurons ◽  
Gnrh Release ◽  
Double Label ◽  
Lh Secretion

In female mammals, increased ovarian estradiol (E2) secretion triggers GnRH release from neurons in the basal forebrain, which drives LH secretion from the pituitary and subsequently induces ovulation. However, the neural circuits that activate this preovulatory GnRH/LH surge remain unidentified. Neurotensin is expressed in neurons of the anteroventral periventricular nucleus (AVPV), a region thought to be critical for generating the preovulatory GnRH/LH surge. E2 induces neurotensin ( Nts) gene expression in this region, and blockade of neurotensin signaling reduces the LH surge in the rat. We postulated that neurotensin signaling plays a similar role in generating the E2-induced GnRH/LH surge in mice. We used in situ hybridization (ISH) to determine whether E2 induces Nts expression in the mouse and found evidence to support this proposition. Next, we determined that the neurotensin receptor (Ntsr2) is present in many GnRH-expressing neurons. Since the kisspeptin gene ( Kiss1) is expressed in the AVPV and is responsive to E2, we predicted that some neurons in this region express both Kiss1 and Nts; however, by double-label ISH, we observed no coexpression of the two mRNAs. We also postulated that Nts mRNA expression would increase in parallel with the E2-induced LH surge and that the central (icv) administration of neurotensin would stimulate LH secretion and activation of GnRH neurons but found no evidence to support either of these hypotheses. Together, these findings suggest that, although neurotensin neurons in the AVPV are targets for regulation by E2, neurotensin does not appear to play a direct role in generating the GnRH/LH surge in the mouse.

scholarly journals Dissecting the Involvement of Arcuate Nucleus Kisspeptin Neurons in Puberty Onset and LH Secretion

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A537-A537
Author(s):  
Eulalia A Coutinho ◽  
Lourdes A Esparza ◽  
Paige H Steffen ◽  
Shreyana Bolleddu ◽  
Alexander S Kauffman
Keyword(s):  
Transition To Adulthood ◽  
Arcuate Nucleus ◽  
Brain Area ◽  
Cell Number ◽  
Pulse Generation ◽  
Juvenile Period ◽  
Lh Surge ◽  
Gnrh Neurons ◽  
Puberty Onset ◽  
Lh Secretion

Abstract Puberty is a crucial period of transition to adulthood, marked by an increased activation of gonadotropin-releasing hormone (GnRH) neurons that drives increased pulsatile secretion of pituitary luteinizing hormone (LH). The mechanisms governing GnRH neuron activation at puberty remain unclear but are likely due to enhanced signaling from upstream neuron populations, including kisspeptin neurons. Kisspeptin (encoded by Kiss1) directly stimulates GnRH neurons to drive GnRH release and downstream LH secretion. Humans and animals with Kiss1 mutations fail to reach puberty, demonstrating kisspeptin’s importance in puberty onset. Nonetheless, the specific brain area(s) from where kisspeptin signaling arises to trigger puberty remain undetermined. Kisspeptin is primarily expressed in two hypothalamic areas, the arcuate nucleus (ARC) and anteroventral periventricular (AVPV) region. ARC Kiss1 neurons are known to drive pulsatile GnRH/LH secretion in both sexes whereas AVPV Kiss1 neurons are sexually dimorphic and mediate the preovulatory GnRH/LH surge in females. We previously showed that Kiss1 gene expression increases in both the ARC and AVPV across the peri-pubertal period, yet it still remains to be determined whether just one or both of these populations is essential for proper pubertal timing. Indeed, the relative involvement of either ARC or AVPV Kiss1 neurons in the pubertal process still remains unknown. Here, we hypothesized that ARC Kiss1 neurons are required for normal puberty timing in both sexes and, conversely, AVPV Kiss1 neurons are not sufficient on their own to trigger normal puberty. To test this hypothesis, we used transgenic mice expressing diphtheria toxin receptor (DTR) exclusively in Kiss1 cells (Kiss Cre/iDTR flox) and took advantage of the differential ontogeny of ARC and AVPV Kiss1 neurons to selectively ablate ARC kisspeptin neurons before puberty, while leaving AVPV neurons intact. We found that targeted deletion of just ARC Kiss1 neurons during the juvenile period (which does not alter AVPV Kiss1 cell number) significantly delays puberty onset in both sexes, as measured by vaginal opening, first estrous, and preputial separation. In addition, these mice also exhibit decreased basal and pulsatile LH secretion in adulthood, further supporting a role for ARC kisspeptin neurons in GnRH pulse generation. By contrast, females with ablated ARC Kiss1 cells still exhibit full estradiol-induced LH surges, ruling out a necessary role of ARC kisspeptin neurons in that process and further supporting AVPV kisspeptin as the primary regulator of the surge. Collectively, our findings demonstrate that ARC Kiss1 neurons are required for both properly timed activation of the reproductive axis during puberty and proper pulsatile LH secretion in adulthood, while AVPV Kiss1 neurons are not sufficient to drive normal puberty onset but are sufficient for the preovulatory LH surge.

scholarly journals Multiple cell types contribute to the atherosclerotic lesion fibrous cap by PDGFRβ and bioenergetic mechanisms

2021 ◽  
Vol 3 (2) ◽  
pp. 166-181 ◽  
Author(s):  
Alexandra A. C. Newman ◽  
Vlad Serbulea ◽  
Richard A. Baylis ◽  
Laura S. Shankman ◽  
Xenia Bradley ◽  
...  
Keyword(s):  
Atherosclerotic Lesion ◽  
Cell Types ◽  
Fibrous Cap ◽  
Multiple Cell

scholarly journals Microtubule–microtubule sliding by kinesin-1 is essential for normal cytoplasmic streaming in Drosophila oocytes

2016 ◽  
Vol 113 (34) ◽  
pp. E4995-E5004 ◽  
Author(s):  
Wen Lu ◽  
Michael Winding ◽  
Margot Lakonishok ◽  
Jill Wildonger ◽  
Vladimir I. Gelfand
Keyword(s):  
Cytoplasmic Streaming ◽  
Cell Types ◽  
Nurse Cells ◽  
Wild Type ◽  
Actin Cortex ◽  
Microtubule Motor ◽  
Multiple Cell ◽  
Cytoplasmic Microtubules ◽  
Two Populations

Cytoplasmic streaming in Drosophila oocytes is a microtubule-based bulk cytoplasmic movement. Streaming efficiently circulates and localizes mRNAs and proteins deposited by the nurse cells across the oocyte. This movement is driven by kinesin-1, a major microtubule motor. Recently, we have shown that kinesin-1 heavy chain (KHC) can transport one microtubule on another microtubule, thus driving microtubule–microtubule sliding in multiple cell types. To study the role of microtubule sliding in oocyte cytoplasmic streaming, we used a Khc mutant that is deficient in microtubule sliding but able to transport a majority of cargoes. We demonstrated that streaming is reduced by genomic replacement of wild-type Khc with this sliding-deficient mutant. Streaming can be fully rescued by wild-type KHC and partially rescued by a chimeric motor that cannot move organelles but is active in microtubule sliding. Consistent with these data, we identified two populations of microtubules in fast-streaming oocytes: a network of stable microtubules anchored to the actin cortex and free cytoplasmic microtubules that moved in the ooplasm. We further demonstrated that the reduced streaming in sliding-deficient oocytes resulted in posterior determination defects. Together, we propose that kinesin-1 slides free cytoplasmic microtubules against cortically immobilized microtubules, generating forces that contribute to cytoplasmic streaming and are essential for the refinement of posterior determinants.

scholarly journals Single-cell mapping of focused ultrasound-transfected brain

Gene Therapy ◽  
2021 ◽  
Author(s):  
A. S. Mathew ◽  
C. M. Gorick ◽  
R. J. Price
Keyword(s):  
Single Cell ◽  
Focused Ultrasound ◽  
Cell Types ◽  
Brain Cell ◽  
Therapeutic Modality ◽  
Full Potential ◽  
Stress Genes ◽  
Multiple Cell ◽  
Differential Gene

AbstractGene delivery via focused ultrasound (FUS) mediated blood-brain barrier (BBB) opening is a disruptive therapeutic modality. Unlocking its full potential will require an understanding of how FUS parameters (e.g., peak-negative pressure (PNP)) affect transfected cell populations. Following plasmid (mRuby) delivery across the BBB with 1 MHz FUS, we used single-cell RNA-sequencing to ascertain that distributions of transfected cell types were highly dependent on PNP. Cells of the BBB (i.e., endothelial cells, pericytes, and astrocytes) were enriched at 0.2 MPa PNP, while transfection of cells distal to the BBB (i.e., neurons, oligodendrocytes, and microglia) was augmented at 0.4 MPa PNP. PNP-dependent differential gene expression was observed for multiple cell types. Cell stress genes were upregulated proportional to PNP, independent of cell type. Our results underscore how FUS may be tuned to bias transfection toward specific brain cell types in vivo and predict how those cells will respond to transfection.

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