Department of Biology

Program

Molecular, Cellular & Developmental Biology

Research Areas

• Developmental Mechanisms and Regulation in Eukaryotic Systems
• Eukaryotic Cell Biology, Cytoskeleton and Signaling

Education

Ph.D., University of California, San Diego, 1996
Postdoctoral Fellow, University of Illinois, 1997-2000
Postdoctoral Fellow, University of California, San Diego, 2001-2007

Awards

American Cancer Society Research Scholar, 2010-2013

Research Description

Metamorphosis of Drosophila photoreceptor cells

An essential feature of photoreceptor cells is the presence of an elaborate membrane structure that houses the millions of receptor proteins required for the detection of light.  Whether it is the rhabdomeres of invertebrate photoreceptors, or the membrane discs of vertebrate photoreceptor cells, these sub-cellular compartments are fundamental not only for photon capture, but in addition for the functional integrity of the photoreceptor neuron. Surprisingly, in spite of their importance -and vital roles- in cell biology and sensory physiology, very little is known about the molecular events choreographing the biogenesis and maintenance of rhabdomeres or outer segments discs.

During Drosophila photoreceptor cell development the apical membrane is transformed into a rhabdomere containing thousands of tightly packed microvilli. In order to identify key components of rhabdomere biogenesis, we searched for loci that affect/control the final morphogenetic state of the photoreceptor cell.  Our screening strategy was based on the observation that defects in rhabdomere morphology often lead to problems in the arrangement of photoreceptors within the ommatidia, a change that can readily be detected by examining the deep pseudopupil (DPP).  Mutations that affect the shape, size or arrangement of the rhabdomeres will result in the absence of a DPP.

Based on this library of mutations, we are focusing on three broad areas with respect to rhabdomere biogenesis.

1. Regulation of microvilli growth. Whether it is the microvilli of rhabdomeres, the brush border of epithelial cells, or the microvillar protrusions that give rise to the membrane discs of vertebrate photoreceptor cells, in all cases these membrane specializations achieve and preserve a stereotypical size and shape.  We have isolated several mutations that affect microvilli length, and currently identifying and characterizing the mutated loci.

2. Transcriptional control of photoreceptor morphogenesis.
The transcriptional control of photoreceptor cell specification is well studied but the control of photoreceptor morphogenesis is less understood.  We have initially characterized one mutation, hazy, that is essential for photoreceptor morphogenesis and function (i.e. rhabdomere biogenesis and phototransduction) but not necessary for specification.  hazy encodes a homeodomain containing transcription factor.  With the use of microarrays, we are currently identifying Hazy transcriptional targets involved in the elaboration of the rhabdomere structure and phototransduction.

3. Protein localization/targeting.  It is evident that many proteins essential for rhabdomere development are segregated to different regions of the transformed apical membrane (spacemaker, crumbs, prominin, chaoptin, etc.). By using various protein tags (e.g. GFP, RFP, and tetracysteine motifs), mutational analysis of the proteins, and comparisons of localization in both wildtype and mutant genotypes we are beginning to unravel the requirements and mechanisms necessary for their specific sub-domain localization.

Select Publications

D. Terrell, B. Xie, M. Workman, S. Mahato, A. Zelhof, B. Gebelein, T. Cook. (2012) OTX2 and CRX rescue overlapping and photoreceptor-specific functions in the Drosophila eye. Den Dyn. Jan;241(1):215-228.

Cook, T *.,Zelhof, A.C.*, Mishra, M., Nie, J. (2011) 800 Facets of Retinal Degeneration. Prog. Mol. Biol. Trans. Sci, 100: 331-368 (* - corresponding authors)

Mishra, M., A. Oke, C. Lebel, E.C. McDonald, Z. Plummer, T.A. Cook, A.C. Zelhof *. (2010) Pph13 and Orthodenticle define a dual regulatory pathway for photoreceptor cell morphogenesis and function. Development.137: 2895-2904. (* - corresponding author)

Cook, B * and Zelhof, A.* , (2008) Photoreceptors in evolution and disease. Nature Genetics 40(11): 1275-1276. (* - corresponding authors)

Zelhof, A.C.  *, R.W. Hardy, A. Becker, C. Zuker (2006) Transforming the architecture of compound eyes. Nature. 443: 696-699. (* - first and corresponding author)

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