Lee Niswander Professor Department of Pediatrics Ph.D., Case Western Reserve Univ, Cleveland, OH, 1990 Pediatrics UCHSC at Fitzsimons RC1 North, Room 4108 P.O. Box 6511, Mailstop 8322 Aurora, CO 80045 Phone: 303-724-3790 Fax: 303-724- Email: Lee.niswander@uchsc.edu

Research in the Niswander lab is focused on the genetic and cellular mechanisms that control embryonic development, particularly the processes required for closure of the neural tube and for development of the vertebrate limb and lung. Our approaches include 1) a forward genetic screen in mice to identify mutations that affect embryonic development; 2) live imaging of the developing neural tube as it closes, of the lung undergoing branching morphogenesis, and of the limb mesenchyme undergoing cartilage formation; and 3) identification of the key kinase and phosphatases that control lung branching morphogenesis.

A forward genetic approach is ideal for identifying key genes that regulate specific developmental processes. Using an ENU (ethylnitrosourea) mutagenesis screen in mice, we have identified a number of recessive mutations that disrupt specific aspects of embryonic development, in particular closure of the neural tube and development of the limb and lung. Although neural tube defects (NTDs) are the second most common human birth defect, the underlying genetic basis of NTDs in humans is poorly understood. Failure to close the neural tube in the brain or spinal cord leads to exencephaly or spina bifida, respectively. We have identified a large number of mouse models of NTD and we are working to identify the genes involved in closure of the neural tube, followed by a comprehensive cellular and molecular characterization of their mechanism of action. Moreover, we wish to understand the mechanism behind the suppression of NTDs by folic acid and to determine whether other dietary supplementations are capable of rescuing the folic acid–resistant NTDs.

From the mutagenesis screen we have identified mutations that affect limb development resulting in polydactyly (extra digits), soft tissue syndactyly (the webbing between the digits does not undergo regression), and other skeletal defects, including shortening or loss of specific limb elements and aberrant cartilage formation. We have also devised a new approach to view limb mesenchyme as it undergoes cartilage formation. This has allowed us to define the cell behaviors involved as these undifferentiated cells undergo the early stages of chondrocyte differentiation. Limb mesenchyme from mutants with an abnormal number of digits and aberrant chondrogenesis will be dynamically imaged to identify the cell behaviors that are disrupted. These studies provide an unbiased means to identify key developmental regulators and will contribute significantly to a greater understanding of the genetic and cellular control of vertebrate limb development.

The lung and other highly branched organs such as the kidney and lacrimal gland develop from a simple epithelial bud into a complex three dimensionally patterned functional organ. This happens through a process called branching morphogenesis. We wish to elucidate the fundamental processes underlying the development of the lung, as well as the pathogenesis of lung disease. To do so we use a combination of forward and reverse genetics in mice and molecular manipulations in organ cultures, coupled with live imaging, to identify key regulators of branching morphogenesis.

Selected Publications

Sears, K.E., Goswami, A., Flynn, J.J. and NISWANDER, L. (2007). The correlated evolution of Runx2 tandem repeats, transcriptional activity and facial length in Carnivora.  Evolution and Development 9, 555-565.

Barna, M. and Niswander, L. (2007). Visualization of cartilage formation: insight into cellular properties of skeletal progenitors and chondrodysplasia syndromes. Developmental Cell 12, 931-941.

Kim, T-H., Goodman, J., Anderson, K.V. and Niswander, L. (2007). Phactr4 regulates neural tube closure by controlling PP1, Rb phosphorylation and cell cycle progression. Developmental Cell 13, 87-102.

Zohn, I.E., Anderson, K.V., and Niswander, L. (2007). The Hectd1 Ubiquitin Ligase is Required for Development of the Head Mesenchyme and Neural Tube Closure. Developmental Biology 306, 208-221.

Zohn, I.E., De Domenico, I., Pollock, A., McVey Ward, D., Goodman, J.F., Liang, X., Sanchez, A.J., Niswander, L., and Kaplan, J. (2007). The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease. Blood 109, 4174-4180.

Sears, K.E., Behringer, R.R., Rasweiler, J.J. IV, and Niswander, L.A. (2007). The evolutionary and developmental basis of parallel reduction in mammalian zeugopod element. The American Naturalist 169, 105-117.

Weatherbee, S.D., Anderson, K.V. and Niswander, L.A. (2006). LDL-receptor-related protein 4 is critical for formation of the neuromuscular junction. Development 133, 4993-5000.

Weatherbee, S., Behringer, R.R., Rasweiler, J.J. and Niswander, L. (2006).  Interdigital webbing retention in bat wings illustrates genetic changes underlying amniote limb diversification. Proc Natl Acad Sci U S A 103, 15103-15107.

Zohn, I.E., Li, Y., Skolnik, E.Y., Anderson, K.V., Han, J. and Niswander, L. (2006). p38 and a p38-interacting protein are critical regulators of E-cadherin downregulation during mouse gastrulation.  Cell 125, 957-969.

Atit, R.P., Sgaier, S.K., Mohamed, O.A., Taketo, M.M., Dufort, D., Joyner, A.L., Niswander, L. and Conlon, R.A. (2006). Beta-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Developmental Biology 296, 164-176.

Sears, K.E., Behringer, R.R., Rasweiler, J.J., and Niswander, L.A. (2006). The Development of Bat Flight: Morphological and Molecular Evolution of Bat Wing Digits. Proc Natl Acad Sci U S A 103, 6581-6586.

Dean, C.H., Miller, L-A., Smith, A.N., Dufort, D., Lang, R.A., and Niswander, L. (2005). Canonical Wnt signaling negatively regulates branching morphogenesis of the lung and lacrimal gland. Developmental Biology 286, 270-286.

Timmer, J., Manova, K., Anderson, K.V. and Niswander, L. (2005). Tissue morphogenesis and vascular stability require the Frem2 protein, product of the mouse myelencephalic blebs gene. Proc Natl Acad Sci U S A 102, 11746-11750.

Barna, M., Pandolfi, P.P. and Niswander. L. (2005). Gli3 and Plzf cooperate in proximal limb patterning at early stages of limb development. Nature 436, 277-281.

Timmer, J., Chesnutt, C. and Niswander, L. (2005). The Activin signaling pathway promotes differentiation of dI3 interneurons in the spinal neural tube. Developmental Biology 285, 1-10.

DiPaola,C.P; Farmer, J.C;  Manova, K., Niswander, L.A. (2005). Molecular signaling in intervertebral disk development. Journal of Orthopaedic Research 23, 1112-9

Liu, A., Wang, B., Niswander, L. (2005). Mouse Intraflagellar Transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development 132, 3103-3111.

Cretekos CJ, Weatherbee SD, Chen CH, Badwaik NK, Niswander L, Behringer RR, Rasweiler JJ 4th. (2005). Embryonic staging system for the short-tailed fruit bat, Carollia perspicillata, a model organism for the mammalian order Chiroptera, based upon timed pregnancies in captive-bred animals. Developmental Dynamics 233, 721-738

Chesnutt, C., Burrus, L. Brown, A.M.C., and Niswander, L. (2004). Coordinate regulation of neural tube patterning and proliferation by TGFb and WNT signaling. Developmental Biology 274, 334-337.

Chesnutt, C. and Niswander, L. (2004). Plasmid-based short-hairpin RNA interference in the chicken embryo. genesis 39, 73-78.

Niemann, S., Zhao, C., Pascu, F., Stahl, U., Aulepp, U., Niswander, L., Weber, J.L., Müller, U. (2004). Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. American Journal of Human Genetics 74, 558-63.

Rouzankina, I., Abate-Shen, C. and Niswander, L. (2004). Dlx genes integrate positive and negative signals during feather bud development.  Developmental Biology 265, 219-233.

Huangfu, D., Liu, A., Rakeman, A. S., Murcia, N. S., Niswander, L. and Anderson, K. V. (2003).  Hedgehog Signaling in the Mouse Requires Intraflagellar Transport Proteins. Nature 426, 83-87.

Reviews and Book Chapters

Weatherbee, S.A and Niswander. L . (2007).  Mechanisms of Chondrogenesis and Osteogenesis in Limbs, in Fins into Limbs.  The University of Chicago Press, 93-102.

Liu, A. and Niswander, L. (2005). Signalling in development: Bone Morphogenetic Proteins in Vertebrate Nervous System Development. Nature Reviews Neuroscience 6. 945-954.

Zohn, I.E., Anderson, K.V. and Niswander, L. (2005). Using genomewide mutagenesis screens to identify the genes required for neural tube closure in the mouse. Birth Defects Res A Clin Mol Teratology 73, 583-90.

Zohn, I. E., Chesnutt, C. R. and Niswander, L. (2003). Cell polarity pathways converge and extend to regulate neural tube closure.  Trends in Cell Biology 13, 451-454.

Niswander, L. (2003). Pattern Formation: old models out on a limb.  Nature Reviews Genetics 4, 133-143.

Latest Publications in PubMed