Jarema Malicki, Ph.D.
Assistant Professor of Ophthalmology
(Genetics)
Harvard Medical
School/MEEI
243 Charles Street
Boston, MA 02114
Tel.: (617) 573-4372
Fax: (617) 573-4290
The laboratory uses the zebrafish retina to study molecular mechanisms fundamental to the development and function of the vertebrate nervous system.
The retina is a relatively simple part of the vertebrate central nervous system. At the onset of neurogenesis, it consists of a morphologically uniform population of neuroepithelial cells. During embryonic development, in a narrow window of about 24 hours, these cells differentiate into several distinct cell classes that are organized in a precise laminar pattern. Each cell class is characterized by a unique morphology, position, and function. Our studies have recently focused on genetic mechanisms that regulate cell polarity in the retina and their role in neurogenesis. Cell polarity is a multifaceted phenomenon that involves, among other processes, the subdivision of the cell membrane into biochemically distinct subdomains, intracellular transport, and cell-cell interactions. Our research focuses mainly on three aspects of cell polarity: apico-basal polarity of neuroepithelia, intraflagellar transport, and the distribution of intracellular organelles.
In an early large-scale genetic screen, we and others uncovered a group of loci that function in the development of the retinal neuroepithelium. Mutations in these genes result in a loss of apico-basal polarity in the epithelium from which the retina differentiates. This phenotype, as well as the molecular structure of the mutant genes, indicate that the determinants of epithelial polarity are closely related in tissues as different as the vertebrate neural tube and Drosophila embryonic epidermis. A good example of that is the nagie oko (nok) locus. While its fly homolog, the stardust gene, is essential for epithelial polarity in the Drosophila embryo, nagie oko plays a very similar, if not identical, role in the polarity of the retinal neuroepithelium. At later stages of neurogenesis, defects in nok activity produce a massive disorganization of neurons, indicating that its function is essential for the formation of gross features of neuronal architecture in the retina, and subsequently for the function of this organ.
The importance of cell polarity is particularly striking in the differentiation of sensory neurons, which frequently feature sophisticated apical specializations. We have shown, for example, that the differentiation and survival of photoreceptor cells, auditory hair cells, or olfactory sensory neurons depend on so-called intraflagellar transport (IFT) genes. We found that defects in a component of the IFT particle encoded by the zebrafish oval locus, lead to the loss of the photoreceptor apical membrane compartment that forms around the apical cilium and is referred to as the outer segment. This compartment stores ca. one billion visual pigment molecules , and is essential for photoreceptor function. Although the ciliary compartments of other sensory neurons, auditory hair cells, and olfactory sensory neurons, are less prominent, in the absence of ovl function these cells too suffer from a loss of cilia and subsequently cell death.
In polarized cells, cytoplasmic organelles are distributed in a defined spatial order, along the apico-basal cell axis. In vertebrate photoreceptors, for example, the nucleus localizes roughly to the center of the cell, apical to the synaptic terminus and basal to the Golgi apparatus as well as the mitochondria-rich inner segment. Defects in the zebrafish mikre oko (mok) locus lead to a severe basal misplacement of photoreceptor cell nuclei. We have recently determined that mok encodes a motor complex component. Together with several other polypeptides that either contribute to the motor complex function or localize to the nuclear envelope, mok determines the position of photoreceptor nuclei. In the absence of mok function, photoreceptor cells die rapidly, possibly due to defects in the differentiation of the synaptic apparatus.
The long-term objective of these studies is to provide a comprehensive picture of the multiple genetic mechanisms that contribute to the establishment and maintenance of cell polarity. The many advantages of the zebrafish model in genetic and embryological studies provide an excellent opportunity to make progress towards this goal. As the eye is remarkably conserved in evolution, the genetic defects in zebrafish frequently resemble human abnormalities and thus can be successfully used as models of human inherited disorders.
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