We study molecular mechanisms that underlie patterning of the vertebrate nervous system during embryonic development.
The foundation of nervous system development is laid during gastrula stages and continues during neurula stages. During this process, part of the embryonic ectoderm (the neurectoderm) is induced and subsequently patterned to form the nervous system. Many regulatory genes are involved in this patterning process, which ultimately allows region-specific differentiation of the neurectoderm into the correct parts of the nervous system. Early players in neural patterning include the genes of the zic family.
One major focus of our work is to understand the roles that the transcription factor zic1 plays during early neural development, using Xenopus and chick embryos as model systems. Developmental genes often play multiple parts throughout development. Similarly, zic1 is involved not only in early patterning of the neural plate, but also in other developmental processes that include induction of the neural crest, formation of the midbrain/hindbrain boundary, in addition to roles in cerebellum, eye, somite, and limb bud development. In order to understand the activities of the zic1 gene at the molecular level, it is of great interest to identify genes that are regulated by this transcription factor. Thus, we have conducted a microarray screen in Xenopus, designed to identify genes that are direct targets of zic1. One of these genes is the novel gene, Xfeb, that may act as a protease and participates in patterning of the hindbrain. Several other genes that we identified, participate in early neural crest formation. Many additional genes from our screen await further study, including genes that point to interesting, previously unknown, activities, in which zic genes may engage.
In other studies, we have shown that zic1 plays a role in the development of the midbrain/hindbrain boundary (MHB). Formation of the boundary between the midbrain (future optic tectum/processing of visual information) and the anterior hindbrain (future cerebellum/coordinated movement, balance) is a critical step in CNS development. The gene interactions that we study at the MHB include how the transcription factor zic1 contributes to formation of the MHB and later to the delay in neuronal differentiation that is characteristic for the MHB. In addition to experiments in whole Xenopus embryos, we are using a tissue explant system to recreate artificial MHBs in vitro that allow the study and manipulation of gene expression in a more controlled environment.
We also focus on the early development of the neural crest and of somites. Several genes that are important for early neural tube formation (including zic genes, wnt genes, etc) are also important for neural crest formation and somite development. Ultimately, we hope to understand the similarities and differences in upstream and downstream regulatory mechanisms that allow these genes to function in such diverse contexts. Our microarray screen is a valuable resource for these studies.
Finally, developmental genes often occur as gene families. The zic gene family comprises five members, which are highly homologous and are expressed in overlapping, but also distinct areas during embryonic development. We are studying these different family members to gain an understanding of their shared and individual contributions to early neural development. These studies may help us understand why our genome devotes five rather redundant genes to the zic gene family.
Overall, the results from our studies will increase our understanding of the molecular mechanisms that underlie early neural development. Our studies will also answer questions about gene families and the multiple roles that developmental genes can play in development.
McMahon, A.R. and C.S. Merzdorf (2010). The Expression of the zic1, zic2, zic3, and zic4 Genes in Early Chick Embryos. BMC Research Notes 3:167.
Cornish, E.J., S.M. Hassan, J.D. Martin, S. Li, and C.S. Merzdorf (2009). A microarray screen for direct targets of Zic1 identifies an aquaporin gene, aqp-3b, expressed in the neural folds. Dev. Dyn. 238:1179-1194.
Merzdorf, C.S. (2007). Emerging roles for zic genes in early development. Dev. Dyn.
Li, S, Y. Shin, K. Cho, and C.S. Merzdorf (2006). The Xfeb gene is directly upregulated by Zic1 in early neural development. Dev. Dyn. Jul 26; Epub ahead of print.
Sun Rhodes, L.S. and C.S. Merzdorf (2006). The zic1 gene is expressed in chick somites but not in migratory neural crest. Gene Expr. Patterns 6:539-545.
Merzdorf, C.S. and H. Sive (2006). The zic1 gene is an activator of Wnt signaling. Int. J. Dev. Biol 50:611-617.
B.S. in Genetics, University of California/Davis
Ph.D. in Cell Biology, Harvard University
Postdoctoral studies in Developmental Biology; Whitehead Institute/Massachusetts Insitute of Technology