Yunus H. Ozekin

University of Colorado Anschutz Medical Campus

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Emily Anne Bates

University of Colorado Anschutz Medical Campus

Mikaela L Follmer

University of Colorado Anschutz Medical Campus

Trevor J. Isner

University of Colorado Anschutz Medical Campus

Emily A. Bates

University of Colorado Anschutz Medical Campus

Kayla Moehn

University of Colorado Anschutz Medical Campus

Laura Faith George

University of Colorado Anschutz Medical Campus

Emily Fontenoy

University of Colorado Anschutz Medical Campus

Maria F. Delgado Figueroa

University of Colorado Anschutz Medical Campus

Claire H Levitt

University of Colorado Denver

Kristen L. Nowak

University of Colorado Denver

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University of Colorado Anschutz Medical Campus

University of Colorado Denver

The Medical Center of Aurora

University of Colorado Health

Rocky Mountain Hospital for Children

Creative Commons

VA Eastern Colorado Health Care System

Hypertension Institute

Children's Hospital Colorado

University of Colorado Boulder

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Depolarization induces calcium-dependent BMP4 release from mouse embryonic palate mesenchyme

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Mikaela L Follmer Trevor J. Isner Yunus H. Ozekin Claire Hoa Levitt Emily Anne Bates

ABSTRACT Ion channels are essential for proper morphogenesis of the craniofacial skeleton. However, the molecular mechanisms underlying this phenomenon are unknown. Loss of the Kcnj2 potassium channel disrupts Bone Morphogenetic Protein (BMP) signaling within the developing palate. BMP signaling is essential for the correct development of several skeletal structures, including the palate, though little is known about the mechanisms that govern BMP secretion. We introduce a tool to image the release of bone morphogenetic protein 4 (BMP4) from mammalian cells. Using this tool, we show that depolarization induces BMP4 release from mouse embryonic palate mesenchyme cells in a calcium-dependent manner. We show native transient changes in intracellular calcium occur in cranial neural crest cells, the cells from which embryonic palate mesenchyme derives. Waves of transient changes in intracellular calcium suggest that these cells are electrically coupled and may temporally coordinate BMP release. These transient changes in intracellular calcium persist in palate mesenchyme cells from embryonic day (E) 9.5 to 13.5 mice. Disruption of Kcnj2 significantly decreases the amplitude of calcium transients and the ability of cells to secrete BMP. Together, these data suggest that temporal control of developmental cues is regulated by ion channels, depolarization, and changes in intracellular calcium for mammalian craniofacial morphogenesis. SUMMARY We show that embryonic palate mesenchyme cells undergo transient changes in intracellular calcium. Depolarization of these cells induces BMP4 release suggesting that ion channels are a node in BMP4 signaling.

Mesenchyme

Calcium in biology

10.1101/2024.06.11.598333

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Citations (1)

Investigating the Effects of Vaping and Nicotine’s Block of Kir2.1 on Humerus and Digital Development in Embryonic Mice

The FASEB Journal (2022)

Kayla Moehn Yunus H. Ozekin Emily A. Bates

Kir2.1 is an ion channel that is important for skeletal development. Nicotine, a common ingredient in electronic cigarettes, blocks Kir2.1. However, little research has been done to investigate how vaping nicotine during pregnancy affects embryonic development. We examined how vaping nicotine during pregnancy would affect embryonic skeletal development in mice. Mice pregnant with embryos of three genotypes-wild-type, Kir2.1+/KO , or Kir2.1KO/KO -received either no vaping treatment, a 2.4% freebase nicotine vaping treatment, or a 3.6% nicotine salt vaping treatment throughout pregnancy. The embryos were dissected at E18.5, and their skeletons were extracted and stained for imaging. The lengths of the humerus bones and number of digital bones were calculated to quantify differences in bone development between groups. We found significant differences in humerus length between the wild-type no vape and wild-type 2.4% freebase nicotine groups, as well as the Kir2.1+/KO no vape and Kir2.1+/KO 2.4% freebase nicotine groups. However, no significant differences were found between wild-type no vape and wild-type 3.6% nicotine salt groups, as well as Kir2.1+/KO no vape and Kir2.1+/KO 3.6% nicotine salt groups. We suspect that nicotine salts are metabolized faster than freebase nicotine and thus inhibit Kir2.1's function for a shorter amount of time, but further research needs to be conducted to test this hypothesis. We conclude that fetal exposure to vaped free base nicotine impacts the development of long bones and reduces long bone length.

Wild type

10.1096/fasebj.2022.36.s1.r2578

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Ion Channel Contributions to Morphological Development: Insights From the Role of Kir2.1 in Bone Development

Frontiers in Molecular Neuroscience (2020)

Yunus H. Ozekin Trevor J. Isner Emily A. Bates

The role of ion channels in neurons and muscles has been well characterized. However, recent work has demonstrated both the presence and necessity of ion channels in diverse cell types for morphological development. For example, mutations that disrupt ion channels give rise to abnormal structural development in species in flies, frogs, fish, mice, and humans. Furthermore, medications and recreational drugs that target ion channels are associated with higher incidence of birth defects in humans. In this review we establish the effects of several teratogens (epilepsy/migraine drugs, nicotine, heat, and cannabinoids) on development. We then propose potential links between these teratogenic agents and ion channels with mechanistic insights from model organisms. Finally, we talk about the role of a particular ion channel, Kir2.1, in the formation and development of bone. Because Ion channels are common targets of many currently used medications, understanding how ion channels impact morphological development will be important for both prevention of birth defects and potentially regenerative medicine. It is becoming increasingly clear that ion channels have functional roles outside of tissues that have been classically considered excitable.

10.3389/fnmol.2020.00099

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Citations (19)

Metabolome Biomarkers of CKD Progression in SPRINT Participants

Journal of the American Society of Nephrology (2024)

Yunus H. Ozekin Zhiying You Kristen L. Nowak Berenice Y. Gitomer Anna Jovanovich

Metabolome

Sprint

10.1681/asn.2024z6dm9a2y

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Intrauterine exposure to nicotine through maternal vaping disrupts embryonic lung and skeletal development via the Kcnj2 potassium channel

Developmental Biology (2023)

Yunus H. Ozekin Maxwell L. Saal Ricardo H. Pineda Kayla Moehn Madison A. Ordonez-Erives

Smoking cigarettes during pregnancy is associated with adverse effects on infants including low birth weight, defective lung development, and skeletal abnormalities. Pregnant women are increasingly turning to vaping [use of electronic (e)-cigarettes] as a perceived safer alternative to cigarettes. However, nicotine disrupts fetal development, suggesting that like cigarette smoking, nicotine vaping may be detrimental to the fetus. To test the impact of maternal vaping on fetal lung and skeletal development in mice, pregnant dams were exposed to e-cigarette vapor throughout gestation. At embryonic day (E)18.5, vape exposed litter sizes were reduced, and some embryos exhibited growth restriction compared to air exposed controls. Fetal lungs were collected for histology and whole transcriptome sequencing. Maternally nicotine vaped embryos exhibited histological and transcriptional changes consistent with impaired distal lung development. Embryonic lung gene expression changes mimicked transcriptional changes observed in adult mouse lungs exposed to cigarette smoke, suggesting that the developmental defects may be due to direct nicotine exposure. Fetal skeletons were analyzed for craniofacial and long bone lengths. Nicotine directly binds and inhibits the Kcnj2 potassium channel which is important for bone development. The length of the maxilla, palatal shelves, humerus, and femur were reduced in vaped embryos, which was further exacerbated by loss of one copy of the Kcnj2 gene. Nicotine vapor exposed Kcnj2

10.1016/j.ydbio.2023.06.002

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Depolarization induces calcium-dependent BMP4 release from mouse embryonic palate mesenchymal cells

Nature Communications (2024)

Mikaela L Follmer Trevor J. Isner Yunus H. Ozekin Claire H Levitt Carolyn L. Burek

Bone Morphogenetic Protein (BMP) signaling is essential for craniofacial development, though little is known about the mechanisms that govern BMP secretion. We show that depolarization induces calcium-dependent BMP4 release from mouse embryonic palate mesenchyme. We show endogenous transient changes in intracellular calcium occur in cranial neural crest cells, the cells from which embryonic palate mesenchyme derives. Waves of transient changes in intracellular calcium suggest that these cells are electrically coupled and may temporally coordinate BMP release. These transient changes in intracellular calcium persist in palate mesenchyme cells from embryonic day 9.5 to 13.5 mice. Disruption of a potassium channel called Kcnj2 significantly decreases the amplitude of calcium transients and the ability of cells to secrete BMP. Kcnj2 knockout mice have cleft palate and reduced BMP signaling. Our data suggest that temporal control of developmental cues is regulated by ion channels, depolarization, and intracellular calcium for mammalian craniofacial morphogenesis. BMP signaling is important for multiple process, including craniofacial development, but relatively little is known about how BMP ligands are secreted. Here they show that embryonic palate mesenchyme cells undergo transient changes in intracellular calcium and that depolarization of these cells induces BMP4 release, suggesting that ion channels are a node in BMP4 signaling.

10.1038/s41467-024-53642-2

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Single cell sequencing of the mouse anterior palate reveals mesenchymal heterogeneity

Developmental Dynamics (2023)

Yunus H. Ozekin Rebecca O’Rourke Emily Anne Bates

Cleft palate is one of the most prevalent birth defects. Mice are useful for studying palate development because of their morphological and genetic similarities to humans. In mice, palate development occurs between embryonic days (E)11.5 to 15.5. Single cell transcriptional profiles of palate cell populations have been a valuable resource for the craniofacial research community, but we lack a single cell transcriptional profile for anterior palate at E13.5, at the transition from proliferation to shelf elevation.

10.1002/dvdy.573

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Citations (13)

Endoplasmic Reticulum Calcium Mediates Drosophila Wing Development

Bioelectricity (2023)

Laura Faith George Mikaela L Follmer Emily Fontenoy Hannah R. Moran Jeremy Brown

The temporal dynamics of morphogen presentation impacts transcriptional responses and tissue patterning. However, the mechanisms controlling morphogen release are far from clear. We found that inwardly rectifying potassium (Irk) channels regulate endogenous transient increases in intracellular calcium and bone morphogenetic protein (BMP/Dpp) release for Drosophila wing development. Inhibition of Irk channels reduces BMP/Dpp signaling, and ultimately disrupts wing morphology. Ion channels impact development of several tissues and organisms in which BMP signaling is essential. In neurons and pancreatic beta cells, Irk channels modulate membrane potential to affect intracellular Ca++ to control secretion of neurotransmitters and insulin. Based on Irk activity in neurons, we hypothesized that electrical activity controls endoplasmic reticulum (ER) Ca++ release into the cytoplasm to regulate the release of BMP.To test this hypothesis, we reduced expression of four proteins that control ER calcium, Stromal interaction molecule 1 (Stim), Calcium release-activated calcium channel protein 1 (Orai), SarcoEndoplasmic Reticulum Calcium ATPase (SERCA), small conductance calcium-activated potassium channel (SK), and Bestrophin 2 (Best2) using RNAi and documented wing phenotypes. We use live imaging to study calcium and Dpp release within pupal wings and larval wing discs. Additionally, we employed immunohistochemistry to characterize Small Mothers Against Decapentaplegic (SMAD) phosphorylation downstream of the BMP/Dpp pathway following RNAi knockdown.We found that reduced Stim and SERCA function decreases amplitude and frequency of endogenous calcium transients in the wing disc and reduced BMP/Dpp release.Our results suggest control of ER calcium homeostasis is required for BMP/Dpp release, and Drosophila wing development.

SERCA

Calcium Signaling

Thapsigargin

Calcium in biology

Morphogen

Decapentaplegic

10.1089/bioe.2022.0036

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Citations (2)