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Mechanisms of Inverted formin 2-mediated intracellular trafficking, invasion, and placentation in mouse and human pregnancy

Lamm, Katherine Young Bezold
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1521191444619542

Abstract Details

2018, PhD, University of Cincinnati, Medicine: Molecular and Developmental Biology.
The biology of human pregnancy and birth relies on the tight regulation and coordination of a diverse array of processes beginning prior to conception with decidualization, followed by implantation and placentation, continuous maternal-fetal crosstalk throughout gestation that extends through labor and parturition. Disruption of any of these processes increases the risk of developing an adverse pregnancy outcome, including hypertensive disorders (5-8% of all pregnancies), intrauterine growth restriction (3-7% of the total population), and preterm birth (9.6% in the USA). However, our current understanding of the molecular mechanisms in the normal as well as the pathological establishment and cessation of this maternal-fetal interface is limited. While it is well established that impaired trophoblast invasion leads to placental ischemia and insufficiency, the mechanisms regulating invasion are unknown. Generation of invasive structures and cell motility is dependent on actin dynamics. The formin family of proteins, known actin regulators, are highly expressed in reproductive tissues and have been implicated in pathological reproduction. We hypothesized that Inverted formin 2 (INF2), a formin with the unique ability to sever and depolymerize actin in addition to traditional functions, is vital for successful pregnancy and parturition. Here, we report that reduction of INF2 alters intracellular trafficking and significantly impairs invasion in a model of human extravillous trophoblasts. Furthermore, global loss of Inf2 in mice recapitulates maternal and fetal phenotypes of placental insufficiency. Inf2-/- dams have reduced spiral artery numbers and late gestational hypertension with resolution following delivery. Inf2-/- fetuses are growth restricted and demonstrate significantly reduced fetal to placental weight ratio, consistent with placental insufficiency in humans. Furthermore, these fetuses demonstrate changes in umbilical artery Doppler consistent with poor placental perfusion and fetal distress. Loss of Inf2 increases fetal vascular density in the placenta and dysregulates trophoblast expression of angiogenic factors. These data support a critical regulatory role for INF2 in trophoblast invasion - a necessary process for placentation. The mechanisms regulating preterm-and, to a large extent, term-birth timing are still unknown. While there is mounting evidence suggesting a genetic contribution to gestation length and preterm birth risk, there is a lack of robust, reproducible associations with specific genes. We have previously reported a significant association between a single nucleotide polymorphism (SNP) near INF2 and preterm birth (PTB) in infants. Using deep sequencing of pooled samples, we report here novel exonic SNPs that may alter INF2 function in preterm infants. SNPs in INF2 have been shown to cause autosomal dominant focal segmental glomerulosclerosis (FSGS); however, it is unknown whether women with these mutations deliver preterm. We report that mice, while engineered to express the INF2 R218Q FSGS mutation, deliver normal litters at term. Others reported no development of FSGS, therefore the use of an alternative model will be needed to elucidate the role of INF2 in PTB. In summary, these studies present a comprehensive interrogation of the role of INF2 in several aspects of pregnancy including placentation and parturition, investigating maternal and fetal phenotypes as well as molecular mechanisms underlying extravillous trophoblast (EVT) invasion.
Louis Muglia, M.D. Ph.D. (Committee Chair)
Stacey Huppert, Ph.D. (Committee Member)
Suhas Kallapur, M.D. (Committee Member)
Satoshi Namekawa, Ph.D. (Committee Member)
Steven Potter, Ph.D. (Committee Member)
140 p.
Molecular Biology
Inverted formin 2; Placental insufficiency; Preterm birth; Intrauterine growth restriction; Extravillous trophoblast invasion; Gestational hypertension

Recommended Citations

Citations

  • Lamm, K. Y. B. (2018). Mechanisms of Inverted formin 2-mediated intracellular trafficking, invasion, and placentation in mouse and human pregnancy [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1521191444619542

    APA Style (7th edition)

  • Lamm, Katherine. Mechanisms of Inverted formin 2-mediated intracellular trafficking, invasion, and placentation in mouse and human pregnancy. 2018. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1521191444619542.

    MLA Style (8th edition)

  • Lamm, Katherine. "Mechanisms of Inverted formin 2-mediated intracellular trafficking, invasion, and placentation in mouse and human pregnancy." Doctoral dissertation, University of Cincinnati, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1521191444619542

    Chicago Manual of Style (17th edition)

ucin1521191444619542
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© 2018, some rights reserved.Creative Commons License Mechanisms of Inverted formin 2-mediated intracellular trafficking, invasion, and placentation in mouse and human pregnancy by Katherine Young Bezold Lamm is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.