Biology subjects

George, L.

Publications and source records attributed to George, L..

3 recordsLinked to original sources

bioRxiv2022

Endometrial adhesion G protein-coupled receptors are dynamically expressed across the menstrual cycle and expression is altered by ovarian stimulation

Ovarian stimulation (OS), utilized for the development of multiple ovarian follicles for IVF, induces supraphysiologic levels of E2 and an early rise in P4 that disrupt endometrial differentiation and decreases implantation rates or result in placental insufficiency and pregnancy complications. To improve pregnancy rates and reduce the risk of pregnancy complications associated with IVF, it is crucial to advance our molecular understanding of the molecular regulation of endometrial differentiation. Previous studies from our laboratory suggest G protein-coupled receptors (GPCRs) are important regulators of endometrial differentiation. To investigate this further, using a retrospective dataset, we identified all GPCRs expressed across the proliferative and secretory phase of the menstrual cycle and found that many members of the adhesion G protein-coupled receptor (ADGR) family are dynamically expressed. For each ADGR subfamily exhibiting differentially-expressed genes across the cycle, their expression was investigated by RT-PCR in the non-pregnant mouse uterus and decidua on E7.5 of pregnancy. For those genes expressed in the E7.5 decidua, their expression was further quantified by qPCR across early mouse pregnancy. The RT-PCR screen revealed expression of 13 ADGRs (4 of the 9 subfamilies) in E7.5 decidua and among these genes, many were differentially expressed between E0.5 and E5.5 or 6.5 and between E5.5 and E6.5. The dynamic expression of the ADGRs across the menstrual cycle and in early mouse pregnancy, suggests these ADGRs are E2- and/or P4-regulated genes. We therefore hypothesized that for these ADGR genes, mRNA expression would be disrupted in an OS cycle. This hypothesis was tested on endometrial biopsies collected in the secretory phase from prospective cohorts of women in natural and OS cycles. Consistent with the retrospective dataset, our data revealed that members of the ADGR gene family are expressed in the secretory phase of the natural menstrual cycle and for the first time, we show that their expression is altered by ovarian stimulation.

cell biology↗

bioRxiv2022

Genetic architecture of spatially complex color patterning in hybrid Mimulus

Coloration in living organisms varies in hue, saturation, and pattern. Here we use genetic mapping to investigate all three elements in monkeyflowers Mimulus luteus var. variegatus and M. cupreus, whose flower petals differ in both yellow carotenoid and magenta anthocyanin pigmentation and whose hybrids exhibit anthocyanin pattern variation not seen in either parent. We report two QTLs associated with carotenoid intensity, and show that lighter yellow petals accumulate relatively high proportions of beta-carotene at the expense of downstream carotenoids. We propose that the derived loss of carotenoid saturation in M. l. variegatus is due to a function-reducing mutation in a Beta-Carotene Hydroxylase candidate gene, coupled with a reduction in the availability of carotenoid-storing chromoplasts influenced by the ORANGE candidate gene. We next identify five QTLs associated with the spatial patterning of anthocyanin pigment. Two QTLs, 9b and 23, each contain genes in the anthocyanin-activating subgroup of the MYB family. We hypothesize that MYB5a/NEGAN, at QTL-9b, activates spot formation in hybrids as part of a Turing-type reaction-diffusion system, while a MYB at QTL-23 activates solid, unpatterned anthocyanin pigment and may also be able to activate the variegatus allele of MYB5a/NEGAN. In addition to the apparently stochastic placement of most spots (consistent with a Turing mechanism), some pattern aspects - notably spots at the petal tips - appear to conform to a positional specification model in which spot location is predetermined. Collectively, this work begins to identify how combinations of yellow and red hues, shifts in carotenoid intensity, and two cryptic patterning systems all contribute to the complexity of color divergence between two close relatives.

genetics↗

bioRxiv2022

Elp1 is required for development of visceral sensory peripheral and central circuitry

Cardiovascular instability and a blunted respiratory drive in hypoxic conditions, are hallmark features of the genetic sensory and autonomic neuropathy, familial dysautonomia (FD). FD results from a mutation in the gene ELP1, whose encoded protein is a scaffolding subunit of the six subunit Elongator complex. In mice, we and others have shown that Elp1 is essential for the normal development of neural crest derived-dorsal root ganglia (DRG) sensory neurons. Whether Elp1 is also required for development of ectodermal placode-derived visceral sensory receptors which are required for normal baroreception and chemosensory responses, has not been investigated. Using mouse models for FD, our data indicate that in fact the entire circuitry underlying baroreception and chemoreception is impaired due to a requirement for Elp1 not only in the visceral sensory neuron ganglia, but also for normal peripheral target innervation, and in their CNS synaptic partners in the medulla. Thus Elp1 is required in both placode- and neural crest-derived sensory neurons and its reduction aborts the normal development of neuronal circuitry essential for autonomic homeostasis and interoception. Summary statementDue to faulty afferent sensory signaling, patients with Familial dysautonomia (FD) have a diminished sensory arm of the baroreflex which would normally modulate blood pressure, and they have a blunted response to hypoxia and hypercapnia (Norcliffe-Kaufmann et al. 2010). Using mouse models for FD, we reveal here the underlying pathology which may underlie these severely impaired homeostatic reflex pathways in FD.

neuroscience↗