Molecular Biology Faculty

Jonathan T. Eggenschwiler

This email address is being protected from spambots. You need JavaScript enabled to view it.	Eggenschwiler Research Lab
(609) 258-7128	Lewis Thomas Lab, 110
	Lab (609) 258-2914
Faculty Assistant	Carolynne Lewis-Arévalo
This email address is being protected from spambots. You need JavaScript enabled to view it.	(609) 258-2933

Research Focus

Genetic analysis of mouse neural development

The processing of information by the nervous system is made possible by the distinct physiological properties of neuronal subtypes and by the complex organization of these cells and their extended cellular processes. In the developing mouse embryo, the generation of this complexity begins from an epithelial sheet of identical, pluripotent cells and proceeds as a result of a myriad of developmental and cellular mechanisms. Although our understanding of these mechanisms is far from complete, some basic principles have emerged. Among these is the notion that specification of discrete neural identities is an important determinant of how a given neuron will behave (e.g., use of specific neurotransmitters or establishment of connectivity). This specification is regulated, in turn, by spatially and temporally restricted signals emanating from the neural progenitor's environment.

Our lab is interested in understanding the molecular basis for these mechanisms through identification of participating components and the assembly of molecular pathways. In vertebrates, this has been traditionally approached starting from candidate genes (such as homologs of genes characterized in Drosophila) and working forward to identify function. We are using a complementary approach, phenotype-driven genetic screens in the mouse, to identify important molecular components of these processes without the bias inherent in the candidate gene approach. In parallel, we are characterizing mouse mutations in known genes, generated through targeted mutagenesis, whose phenotypes link them to neural patterning.

The open brain/Rab23 gene is one example of such an unexpected component. Open brain (opb) mutants exhibit a variety of developmental abnormalities affecting the neural tube, limbs, eyes, somites and neural crest derivatives. The mutant spinal cord shows global misspecification of cell identities along the dorsal-ventral axis; cell fates are inappropriately ventralized. The hedgehog signaling pathway plays a crucial role in specifying ventral neural fate and the principal ligand in this context is Sonic Hedgehog (SHH). SHH is produced by cells at the ventral pole of the neural tube and is thought to function as a classical morphogen by specifying different cell fates as a function of the protein's graded distribution. The gene disrupted in opb mutants encodes Rab23, a member of the Rab family of vesicle-trafficking proteins. Our analysis has shown that Rab23 functions in hedgehog-responsive cells as an antagonist that keeps this signaling pathway inactive in the absence of the ligand. These experiments also revealed the existence of other, yet unidentified, positional cues that regulate discrete fates along the dorsal-ventral axis. One aspect of our current work is aimed at clarifying the molecular role of Rab23 in the hedgehog pathway.

Our genetic screens and characterization of knockout mice have identified additional genes required for dorsal-ventral patterning of the early neural tube. We are using genetic, cellular, and biochemical approaches to clarify the functions of the gene products. Unexpectedly, many of these genes appear to encode novel components that have evolved to function in hedgehog signaling since the mammalian and invertebrate lineages diverged. This serves to underscore the importance of using mammalian systems to accurately model the hedgehog pathway in humans, as direct comparison between the mammalian and invertebrate signaling pathways is not always possible.

Selected Publications

Qin, J, Lin Y, Norman, RX, Ko HW, Eggenschwiler, JT. Intraflagellar transport protein 122 antagonizes Sonic Hedgehog signaling and controls ciliary localization of pathway components. Proc Natl Acad Sci. 108: 1456-1461. PubMed

Walczak-Sztulpa J, Eggenschwiler J, Osborn D, Brown DA, Emma F, Klingenberg C, Hennekam RC, Torre G, Garshasbi M, Tzschach A, Szczepanska M, Krawczynski M, Zachwieja J, Zwolinska D, Beales PL, Ropers HH, Latos-Bielenska A, Kuss AW. Cranioectodermal Dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene. (2010). Am J Hum Genet. 86: 949-956. PubMed

Ko HW, Norman RX, Tran J, Fuller KP, Fukuda M, Eggenschwiler JT. (2010) Broad-minded links cell cycle-related kinase to cilia assembly and Hedgehog signal transduction. Dev. Cell 18: 237-247 PubMed

Ko HW, Liu A, Eggenschwiler JT. (2009) Analysis of hedgehog signaling in mouse intraflagellar transport mutants. Meth. Cell Biol. 93: 347-369. PubMed

Norman RX, Ko HW, Huang V, Eun CM, Abler LL, Zhang Z, Sun X, and Eggenschwiler JT. (2009). Tubby-like protein 3 (TULP3) regulates patterning in the mouse embryo through inhibition of Hedgehog signaling. Human Mol Genet. 18: 1740-1754. PubMed

Cho A, Ko HW, Eggenschwiler JT. (2008) FKBP8 cell-autonomously controls neural tube patterning through a Gli2- and Kif3a-dependent mechanism. Dev Biol. 321: 27-39. PubMed

Eggenschwiler JT, Anderson KV. (2006) Cilia and Developmental Signaling. Annu Rev Cell Dev Biol 23: 345-373. PubMed

Eggenschwiler JT, Bulgakov OV, Qin J, Li T, Anderson KV. (2006) Mouse Rab23 regulates hedgehog signaling from smoothened to Gli proteins. Dev Biol 290: 1-12. PubMed

Garcia-Garcia MJ, Eggenschwiler JT, Caspary T, Alcorn HL, Wyler MR, Huangfu D, Rakeman AS, Lee JD, Feinberg EH, Timmer JR, Anderson KV. (2005) Analysis of mouse embryonic patterning and morphogenesis by forward genetics. Proc Natl Acad Sci USA 102: 5913-5919. PubMed

Bulgakov OV, Eggenschwiler JT, Hong DH, Anderson KV, Li T. (2004) FKBP8 is a negative regulator of mouse sonic hedgehog signaling in neural tissues. Development 131: 2149-2159. PubMed

Caspary T, Garcia-Garcia MJ, Huangfu D, Eggenschwiler JT, Wyler MR, Rakeman AS, Alcorn HL, Anderson KV. (2002) Mouse Dispatched homolog1 is required for long-range, but not juxtacrine, Hh signaling. Curr Biol 12: 1628-1632. PubMed

Eggenschwiler JT, Espinoza E, Anderson KV. (2001) Rab23 is an essential negative regulator of the mouse Sonic hedgehog signalling pathway. Nature 412: 194-198. PubMed

Eggenschwiler JT, Anderson KV. (2000) Dorsal and lateral fates in the mouse neural tube require the cell-autonomous activity of the open brain gene. Dev Biol 227: 648-660. PubMed

Eggenschwiler J, Ludwig T, Fisher P, Leighton P, Tilghman S and Efstratiadis A. (1997) Mouse mutant embryos overexpressing IGF-II exhibit phenotypic features of the Beckwith-Wiedemann and Simpson-Golabi-Behmel syndromes. Genes Dev. 11: 3128-3142.

Ludwig T, Eggenschwiler J, Fisher P, D'Ercole AJ, Davenport ML and Efstratiadis A. (1996) Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds. Dev Biol. 177: 517-535.

Leighton PA, Ingram RS, Eggenschwiler J, Efstratiadis A and Tilghman SM. (1995) Disruption of imprinting caused by deletion of the H19 gene region in mice. Nature 375: 34-39.