Position title: Professor
Phone: Phone: (608) 265-5411
RESEARCH INTERESTS - Development of the fetal-placental connection
B.S., 1978, University of Illinois, Chicago, IL, Biology
M.S., Ph.D., 1980, 1984, University of Illinois, Chicago, IL, Genetics
Post-Doc., 1984-1988, University of California-San Francisco, CA, Molecular Biology
Post-Doc., 1989-1993, University of Oxford, England, Mouse Embryology
The primitive streak is one of the most important, yet enigmatic, structures of amniote species. The streak establishes the anteroposterior embryonic body axis, and provides a conduit through which embryonic mesoderm and endoderm are formed. Whilst the streak’s anterior end, called the node, has been the subject of countless investigations over the past decades, the whereabouts of the posterior primitive streak have not been satisfactorily identified in any species.
Using a combination of classical methods of experimental embryology in living embryos, genetics, and protein localization, we have discovered that the primitive streak’s posterior limit is not confined to the embryo proper. Rather, contrary to conventional wisdom, it extends into the extraembryonic region. There, it establishes both the allantois, or umbilical component of the chorio-allantoic placenta, and a self-contained cell reservoir that bears the hallmarks of a stem cell niche. This niche, called the “allantoic core domain” (ACD), is essential for allantoic elongation to the chorion to ensure placentation. In addition, a variety of allantoic and embryonic cell types, including the primordial germ cells, may be specified and deployed from it. By contrast, the intraembryonic posterior component of the primitive streak contributes cells to the allantoic cell surface which, over time, extend to the embryonic body wall and gut.
We propose that defects in the posterior primitive streak’s components, and/or the structures established by them, lead to a spectrum of umbilical-associated embryonic birth defects which fall into the category of “orphan” diseases, as their underlying etiologies are largely unknown. Many of these involve the embryonic midline, and include the caudal body wall, gastrointestinal and reproductive systems. Our immediate goals are to elucidate the properties of the posterior primitive streak, and the cells deployed by the ACD. Our long term goals are to discover the steps by which the streak provides the developmental link between the embryo and its umbilical cord, thereby ensuring a proper fetal/maternal relationship.
The murine allantois is architecturally complex. Bright-field histological section (A) and schematic diagram (B) of a headfold-stage allantois shows the relationship between the Allantoic Core Domain (ACD), distal squamous mesothelium (m), Ventral Cuboidal Mesothelium (VCM), Dorsal Cuboidal Mesothelium (DCM), the amnion (am) and the intraembryonic primitive streak (ps). The chorionic and anterior components of the conceptus are not shown in (A).
Other abbreviations: AC, amniotic cavity; AX, allantois-associated extraembryonic visceral endoderm; b, visceral yolk sac blood island; ce, chorionic ectoderm; ch, chorion; cm, chorionic mesoderm; dal, distal allantois; e, epiblast; EC, ectoplacental cavity; ee, ectoplacental endoderm; vys, visceral yolk sac; X, exocoelomic cavity. For simplicity, the anterior embryonic region is not shown in this diagram. A, anterior embryonic side; P, posterior embryonic side. Dist, distal allantoic end; Prox, proximal allantoic end. (Modified from Inman and Downs, 2007).
- Mikedis, M. M. and Downs, K. M. (2017) PRDM1/BLIMP1 is widely distributed to the nascent fetal-placental interface in the mouse gastrula. Dev. Dyn. 246, 50-71.
- Wolfe, A. D., Rodriguez, A. M. and Downs, K. M. (2017) STELLA collaborates in distinct mesendodermal cell subpopulations at the fetal-placental interface in the mouse gastrula. Dev. Biol., in press.
- Rodriguez, A. M., Jin, D. X., Mikedis, M. M., Wolfe, A. D., Hashmi, M., Wierenga, Viebahn, C., and Downs, K. M. (2017) BRACHYURY drives formation of a distinct vascular branchpoint critical for fetal-placental arterial union and patterning in the mouse. In revision.
- Nelson DO, Lalit PA, Biermann M, Markandeya YS, Capes DL, Addesso L, Patel G, Han T, John MC, Powers PA, Downs KM, Kamp TJ, Lyons GE. (2016) Irx4 Marks a Multipotent, Ventricular-Specific Progenitor Cell. Stem Cells. 34(12):2875-2888.
- Lalit PA, Salick MR, Nelson DO, Squirrell JM, Shafer CM, Patel NG, Saeed I, Schmuck EG, Markandeya YS, Wong R, Lea MR, Eliceiri KW, Hacker TA, Crone WC, Kyba M, Garry DJ, Stewart R, Thomson JA, Downs KM, Lyons GE, Kamp TJ. (2016) Lineage Reprogramming of Fibroblasts into Proliferative Induced Cardiac Progenitor Cells by Defined Factors. Cell Stem Cell. 18:354-67.
- Wolfe, A. C. and Downs, K. M. (2014). Mixl1 localizes to putative axial stem cell reservoirs and their posterior descendants in the mouse. Gene Exp Patterns. 15:8-20.
- Mikedis MM, Downs KM. (2014) Mouse primordial germ cells: a reappraisal. Int Rev Cell Mol Biol. 309:1-57.
- Nelson DO, Jin DX, Downs KM, Kamp TJ, Lyons GE. (2014) Irx4 identifies a chamber-specific cell population that contributes to ventricular myocardium development. Dev Dyn. 243:381-92.
- Mikedis, M. M. and Downs, K. M. (2013). Widespread but tissue-specific patterns of interferon-induced transmembrane protein 3 (IFITM3, FRAGILIS, MIL-1) in the mouse gastrula. Gene Expr. Patterns 13, 225-239.
- Stern CD, Downs KM. (2012) The hypoblast (visceral endoderm): an evo-devo perspective. Development. 139:1059-69.
- Mikedis, M. M. and Downs, K. M. (2012). STELLA-positive subregions of the primitive streak cooperate to build the posterior region of the murine conceptus. Dev. Biol., 363, 201-218.
- Daane, J. M. and Downs, K. M. (2011). Hedgehog signaling in the posterior region of the mouse gastrula suggests manifold roles in the fetal/umbilical connection and posterior morphogenesis. Dev. Dyn. 240, 2175-2193
- Daane, J. M., Enders, A. C.and Downs, K. M. (2011). Mesothelium of the murine allantois exhibits distinct regional properties. J. Morph. 272, 536-556
- Mikedis, M.M. and Downs, K.M. (2009). Collagen type IV and Perlecan exhibit dynamic localization in the Allantoic Core Domain, a putative stem cell niche in the murine allantois. Dev. Dyn. 238, 3193-3204
- Downs, K.M., Inman, K.E., Jin, D.X., and Enders, A.C.,(2009). The Allontoic Core Domain (ACD): New insights into development of the murine allantois and its relation to the primitive streak. Dev. Dyn. 238, 532-553
- Downs, K.M. (2008) Systematic localization of Oct-3/4 (Pou5f1) to the gastrulating mouse conceptus suggests manifold roles of Oct-3/4 in mammalian development. Dev.Dyn., 237, 464-474
- Ziegler, B.M., Sugiyama, D., Chen, M., Guo, Y., Downs, K.M., and Speck, N.A. (co-corresponding authors) (2006). The allantois and chorion, isolated before circulation or chorio-allantoic fusion, have hemtopoietic potential. Development 133, 4183-4192 (Featured in “In This Issue”)
- Inman, K.E. and Downs, K.M. (2006) Brachyury is required for elongation and vasculogenesis in the murine allantois. Development, 133, 2947-2959
- Inman, K.E. and Downs, K.M. (2006). Spatiotemporal localization of Brachyury (T) in the embryonic and extraembryonic tissues of the mouse gastrula. Gene Exp. Patterns, 6,788-793
- Downs, K. M., McHugh, J., Barrickman, K., Hellman, E. and Inman, K. (2004) Investigation into a role for the primitive streak in development of the murine allantois. Development 131, 37-55.
- Downs, K. M., Temkin, R., Gifford, S. and McHugh, J. (2001). Study of the murine allantois by allantoic explants. Dev. Biol. 233, 347-364.
- Downs, K. M., Gifford, S., Blahnik, M. and Gardner, R. L. (1998). Vascularization in the murine allantois occurs by vasculogenesis without accompanying erythropoiesis. Development 125, 4507-4520.
- Downs, K. M. and Harmann, C. (1997). Developmental potency of the murine allantois. Development 124, 2769-2780.
- Downs, K. M. and Gardner, R. L. (1995). An investigation into early placental ontogeny: allantoic attachment to the chorion is selective and developmentally-regulated. Development 121, 407-416
- Downs, K.M. and Davies, T. (1993). Staging of gastrulation in mouse embryos by morphological landmarks in the dissection microscope. Development 118, 1255-1266
- Downs, K.M., Martin, G.M., and Bishop, J.M. (1989). Contrasting patterns of myc and N-myc expression during gastrulation of the mouse embryo. Genes Dev. 3: 860-869
Relevant Methods and Reviews
- Lalit, P. A., Rodriguez, A. M., Downs, K. M., and Kamp, T. J. (2017). Generation of expandable, multipotent induced cardiac progenitor cells from mouse fibroblasts and potency testing in ex vivo embryos. Nature Protocols, in press.
- Mikedis, M.M. and Downs, K. M. (2014) Invited Review: Mouse primordial germ cells: a reappraisal. Int. Rev. Cell Mol. Biol., in press.
- Stern, C. D. and Downs, K. M. (2011). Hypoblast (visceral endoderm): an evo-devo perspective. Development, in press.
- Downs, K. M. (2009) Invited Peer-Reviewed Hypothesis: The enigmatic primitive streak: Prevailing notions and challenges concerning the embryonic body axis. BioEssays 31, 892-902.
- Inman, K.E. and Downs, K.M. (2007). Invited Review: The murine allantois: emerging paradigms in formation and development of the mammalian umbilical cord and its relation to the fetus. Genesis 45, 237-258.
- Downs, K. M. (2004). Invited book chapter: Extraembryonic tissues. In Gastrulation , C. Stern, ed. (Cold Spring Harbor, New York: Cold Spring Harbor Press), pp. 449-459
- Downs, K.M. (1998). Invited review: The murine allantois. In Current Topics in Developmental Biology, R. Pedersen and G. Schatten, eds. (San Diego: Academic Press), 39, 1-33.
- Downs, K. M. (2005). Invited Review: In vitro culture model for studying allantoic vasculogenesis and fusion with the chorion. In Placental and Trophoblast Methods and Protocols for Methods in Molecular Medicine Series, M. J. Soares and J. Hunt, eds. (Totowa, JH: Humana Press, Inc.), 121, 241-272.