Zebrafish: a model for the neurodevelopmental causes of Prader-Willi syndrome?

Jennifer L. Unger and Eric Glasgow

Department of Neurobiology, Northeastern Ohio Universities College of Medicine, Rootstown, OH and the Graduate Program in Cellular and Molecular Biology, School of Biomedical Sciences, Kent State University, Kent, OH

 Zebrafish are an ideal model for many aspects of brain development because of the many experimental advantages of this animal.  These advantages include the ability to perform large-scale genetic screens, targeted loss and gain of function assays and embryological manipulations.  We have characterized the development of isotocin producing cells in zebrafish as a paradigm for the molecular control of hypothalamic development.  Zebrafish isotocin is orthologous to mammalian oxytocin.  We have identified five transcriptional regulatory genes involved in isotocin cell development.  These are the homeobox genes pou47, brn1.2 and otp, and the basic helix-loop-helix PAS genes sim1 and arnt2.  We have also examined the interactions among these genes by whole-mount in situ hybridization and immunohistochemistry in conjunction with antisense Morpholino oligonucleotide targeted loss of function experiments. The results of these experiments demonstrate that the genes controlling isotocin cell development are structurally and functionally conserved between zebrafish and mammals.

In Prader-Willi syndrome there is altered development of the hypothalamus through a reduction in both the total number of cells and oxytocin-containing cells in the paraventricular nucleus.  The transcriptional regulatory gene sim1 is required for oxytocin cell development in mice.  Likewise, we have shown that sim1 is required for isotocin cell development in zebrafish.  It is important to note that haploinsuffiency of sim1 leads to obesity in humans, further linking the molecular control of oxytocin cell development to Prader-Willi syndrome.  Further research is needed in order to understand the underlying molecular genetic basis of oxytocin/isotocin cell development.  We will discuss the potential for using zebrafish to accelerate this research, focusing on the possibilities of: 1) identifying additional genes involved in isotocin cell development by mutagenesis screening; and 2) rapidly evaluating the functions of candidate isotocin cell regulatory genes.  Understanding the molecular genetic control of isotocin cell development will identify candidate genes and pathways involved in Prader-Willi syndrome, and perhaps lead to novel therapeutic approaches to this disorder.

June 2004