Sive Lab research is supported in part by grants from
the National Institutes of Health and National Science Foundation

Alicia Blaker

Autism is associated with profoundly debilitating social and physical symptoms, and can manifest by 12 months of age. A significant fraction of autistic patients show recurrent copy-number variations, affecting genes whose dosage may be crucial in normal brain development and function. We are using the zebrafish as a tool to define the functions of these autism-associated genes. We define a tool as a system that allows insight into a human disorder, but does not phenocopy the disorder. This is in contrast to a model which specifically phenocopies the human disorder. The tool is used for its attributes, which, in the case of the zebrafish, include rapid development and therefore, rapid assays, ability to image at single cell resolution, availability of molecular and genetic tools, and ability to perform chemical screens. We hypothesize that zebrafish homologs of human autism-associated genes will function during brain development, and that their function will be orthologous to those of corresponding human genes.



Jessica Chang

The brain ventricular system is a system of highly conserved cavities, that contain cerebrospinal fluid, which is essential for brain function. Although the embryonic brain ventricles contain very large amounts of embryonic CSF (eCSF) little is known about how this fluid is secreted or how it functions. We are using the zebrafish to define the mechanisms underlying eCSF function and ventricle inflation. We previously showed that the Na+ K+ ATPase alpha subunit, atp1a1, is required for zebrafish brain ventricle inflation (Lowery and Sive 2005) and are currently investigating the role of the Na+ K+ ATPase in regulation of brain ventricle size which has implications for the etiology of hydrocephalus.



Gianluca De Rienzo

I am using the zebrafish as a novel “tool” to address gene function underlying mental health disorders. This is in contrast to the notion of a “model” system, which implies that a non-human animal phenocopies the human syndrome. The limited range of behaviors available to the fish, prevents this from being a model for mental health disorders, per se. Rather, the term “tool” implies using an animal system to its best advantage. In the case of the zebrafish, this includes ability to perform rapid loss of function assays, using antisense techniques, and ability to image at single cell resolution in the living embryo, as it is transparent. Many hundreds of embryos can be obtained daily, which together with their small size, makes medium-scale chemical screening feasible. Most human genes have clear zebrafish homologs. Brain structure is largely conserved between mammals and fish, although the fish has a much smaller forebrain than mammals. Fish embryos develop rapidly, with the first neurons born by 18 hours post fertilization (hpf), and a well-developed brain present by 24 hpf.

In addition, I am using the fish to identify small molecules that modulate phenotypes caused by changes in disorder gene function. These screens may suggest potential therapeutics for mental health disorders.



Amanda Dickinson

The broad goals of my research are to understand craniofacial development, specifically the mechanisms by which the primary mouth develops. The primary mouth is the first opening between the foregut and the external environment. It forms from a unique and well conserved region where ectoderm and endoderm are directly apposed. In most invertebrates the primary mouth remains the mouth in the adult. Yet, in the vertebrates, with the advent of the neural crest, an extensive elaboration of the craniofacial region including teeth, jaws, and tongue encase the primary mouth to form a new adult or secondary mouth. Primary mouth formation is of interest for several reasons. First, the mechanism by which this essential craniofacial structure forms is of intrinsic importance to normal development since abnormalities in primary mouth development result in craniofacial defects. Second, we have proposed that the primary mouth is derived from a common extreme anterior domain that is conserved across deuterostomes (Dickinson and Sive, 2007). Thus, an analysis of primary mouth formation in related animals will make important contributions to understanding evolution of the facial region.

Our first study described the morphological changes and tissue requirements in primary mouth formation in the model vertebrate Xenopus laevis (Dickinson and Sive, 2006).

To find candidate regulators of the steps governing primary mouth formation, I used an unbiased microarray approach and identified 40 genes specifically enriched in the region. The most highly enriched in the presumptive primary mouth is frzb-1, a member of a large class of Wnt antagonists. Our next study focused on the role of the related Wnt antagonists Frzb-1 and Crescent. We demonstrated that these genes function together to inhibit Wnt/?-catenin signaling and govern basement membrane dissolution in the early stages of primary mouth development (Dickinson and Sive, 2009).



Dickinson, A. J. and Sive, H. L. (2006). Development of the primary mouth in Xenopus laevis. Dev Biol 295, 700-13.
Dickinson, A. J. and Sive, H. L. (2007). Positioning the extreme anterior in Xenopus: cement gland, primary mouth and anterior pituitary. Semin Cell Dev Biol 18, 525-33.
Dickinson, A. J. and Sive, H. L. (2009). The Wnt antagonists Frzb-1 and Crescent locally regulate basement membrane dissolution in the developing primary mouth. Development 136, 1071-81.


Ellie Graeden

Bends and folds in the neuroepithelium surrounding the developing brain ventricles delineate functional brain regions and angle the brain to effectively pack into the skull. The midbrain-hindbrain boundary (MHB) is one such highly conserved, major early brain constriction. At the caudal end of the midbrain, the neuroepithelium is constricted from the outside of the tube. This constriction is formed by a sharp bend in the basal surface of the epithelial sheet. I am interested in the process by which such a constriction forms from the early patterning events long before morphogenesis to the cell length and shape changes required to undergo this neuroepithelial morphogenesis. In a recent study in collaboration with Dr. Jennifer Gutzman, also in the Sive lab, we have shown that the MHB forms in a two-step process including an initial shortening of the cells followed by a formation of wedge-shaped cells constricted at their basal surface. The basal lamina lines the outside of the neural tube, and we have determined that one major component of the basal lamina, laminin, while dispensable for the cell shortening, is required for the subsequent basal constriction. This morphogenesis is independent of ventricle inflation. In future studies, I hope to elucidate the functional connections between the early patterning events at the MHB to these later morphogenic steps.

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