Christopher Kintner
e-mail: kintner@salk.edu |
 |
Our research interests concern the first steps
in the formation of the vertebrate nervous system during which a region
of the ectoderm forms the neural plate and gives rise to neural tissue,
rather than differentiating into epidermis. We study, at the molecular
level, how changes in cell fate, and tissue morphogenesis underlie
these early stages in the formation of the vertebrate nervous system.
We study these events in the frog embryo Xenopus laevis, because
of their experimental accessibility,
especially in terms of studying gene function.
The neurons that comprise neural tissue
are generated from the neurogenic epithelium of the neural plate and
tube. In Xenopus embryos, this process begins extremely early
in development within defined domains of the neural plate, thereby
generating the three classes of neurons (motor, inter-, and sensory
neurons) which form the so-called primary nervous system. The small
number and simple spatial layout of primary neurons has made them
an attractive system for studying the mechanisms that
operate during neurogenesis. Indeed by using the primary neurons as
an assay for gene function, several of the key molecules that regulate
the number, spatial distribution, and types of neurons produced during
primary neurogenesis has now been identified.
Formation of primary neurons in Xenopus embryos. Whole-mount in situ hybridization using a type II neural specific tubulin probe reveals the pattern of primary neurons in the neural plate, including primary motor neurons (M), interneurons (I) and sensory neurons (L).
The formation of primary neurons is promoted by a bHLH protein called Neurogenin. Current studies are aimed at understanding further the mechanism that determine whether cells undergo neuronal differentiation in response to Neurogenin or lateral inhibition in response to Notch activation.
In addition to regulating neuronal differentiation, the Notch pathway has also been found to play an important role in the process of segmentation. In vertebrates, segmentation occurs within the paraxial mesoderm in a rostral-caudal progression, ultimately producing segmental structures called somites. A number of the genes that regulate neuronal differentiation have counterparts that are expressed within the paraxial mesoderm during the time when a segmental pattern is laid down. Current studies are aimed at understanding how these genes function to produce a segmental pattern.
During the early stages in the formation
of the central nervous system, extensive tissue remodelling takes
place as the neural plate forms and undergoes neurulation to form
the neuroepithelium of the neural tube. These morphological changes
are mediated in part by changes in the adhesive properties of cells.
To study these changes, we have identified and characterized cell
surface proteins belonging to the cadherin superfamily which mediate
adhesion between embryonic cells. These molecules
are expressed in a dynamic fashion both temporally and spatially during
the early formation of the vertebrate nervous system, and perturbing
their function results in abnormal tissue structure. We are dissecting
the role of these molecules in tissue morphogenesis by identifying
molecules that interact with the cadherin cytoplasmic domain, by studying
how these molecules regulate cell rearrangements during morphogenesis,
and by determining how these molecules become expressed in different
subregions of the neural tube.
Espeseth, A., Marnellos, G. and Kintner, C. (1998). The role of F-cadherin in localizing cells during neural tube formation in Xenopus embryos. Development 125:301-12.
Bradley, R. S., Espeseth, A. and Kintner, C. (1998). NF-protocadherin, a novel member of the cadherin superfamily, is required for Xenopus ectodermal differentiation. Current Biology 8: 325-34.
Wettstein, D.A., Turner, D.L. and Kintner, C. (1997). The Xenopus homolog of Drosophila Suppressor of Hairless mediates Notch signaling during primary neurogenesis. Development 124:693-702.
Jen, W.C., Wettstein, D., Turner, D., Chitnis, A. and Kintner, C. (1997). The Notch ligand, X-Delta-2, mediates segmentation of the paraxial mesoderm in Xenopus embryos. Development 124:1169-78.
Bellefroid, E. J., Bourguignon,
C., Hollemann, T., Ma, Q., Anderson, D.,J., Kintner, C. and Pieler,
T. (1996). X-MyT1, a Xenopus C2HC-Type zinc finger protein with a
regulatory function in neuronal differentiation. Cell 87:1191-1202.
Chris Kintner received his Ph.D. from the University of Wisconsin, Madison. He has been a research scholar of both the Sloan and the McKnight Foundations.
