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Joseph Brzezinski, Ph.D.

Joseph Brzezinski, Ph.D.
Background 

The retina is a thin nervous tissue that lines the back of the eye and is responsible for detecting and relaying light stimuli to the brain.  The retina is made up of seven principal cell types arranged into three layers (Figure 1).  These include rod and cone photoreceptors; amacrine, bipolar, and horizontal interneurons; retinal ganglion cells (RGCs); and Müller glia.  Rod photoreceptors  are very sensitive to light and are responsible for night vision.  These are the most abundant cell type in the human retina and are located closest to the back of the eye, near the retinal pigmented epithelium (RPE).  Cone photoreceptors are responsible for high acuity vision (like reading) and color discrimination.  There are three types of cones in the human retina, each attuned to a specific wavelength of light (blue, green, red).  Photoreceptors send their signals via bipolar interneurons.  These signals are then relayed to the brain via RGCs.  Horizontal and amacrine interneurons modulate signaling between photoreceptors, bipolars, and RGCs.  Lastly, Müller glia maintain the retinal neurons and establish a blood-retinal barrier between the vasculature and the neurons.  Each of these cell types is important for normal vision. 

Other cell types are present in the retina as well.  The retina is perfused by blood vessels which form three layers (plexi).  Two of the vascular plexi are deep inside the retina and one is near the inner surface of the retina (Figure 1).  These vessels are made up of vascular endothelial cells and mural cells.  Retinal astrocytes coat the surface of the retina and form a blood-retinal barrier with the surface vasculature (Figure 1).  Müller glia form a blood-retinal barrier with the deep plexi.  On a per weight basis, the retina is the most metabolically active tissue in the body.  Thus, the nourishment provided by the retinal vasculature is critical for normal vision.  The retina is also populated with microglia, which act as phagocytes (eating cells) and are similar to macrophages of the immune system. 

There are many diseases that affect the retina (Figure 2).  These diseases can affect neurons directly or other structures in the eye such as the vasculature or the RPE.  If the disease process causes the death of retinal neurons, permanent vision loss can occur since neurons are not replaced.  For example, age-related macular degeneration (AMD) results in permanent loss of photoreceptors and significant visual impairment due to RPE and/or vascular alterations (Figure 2).  In diabetic retinopathy, the retinal vasculature is affected and retinal neurons are progressively lost (Figure 2).  Patients with glaucoma (Figure 2) permanently lose their RGCs and cannot relay photic information to the brain.  Less commonly, there are diseases caused by defects in genes that control the development and/or function of specific populations of retinal neurons.  For example, mutations in genes that control photoreceptor function cause retinitis pigmentosa or Leber’s congenital amaurosis; each of which result in progressive photoreceptor loss (Figure 2) (Dr. James Friedman).  How can vision be restored to people who have permanently lost retinal neurons?  The key lies in discovering how these cells develop.  

The entire complement of retinal neurons is formed before we are born.  The retina starts out as a population of progenitor cells (similar to stem cells).  These progenitors are multipotent, that is they can become any of the seven principal cell types of the retina.  Over time, these progenitors permanently exit the cell cycle (stop dividing) and differentiate (mature) into neurons and glia.  Different cell types are formed at different times.  For example RGCs are formed early and glia are formed late in development.  While there is a trend to when each cell type is formed, there is considerable overlap such that multiple cell types are forming at any given time.  How do these progenitors decide which type of cell to become (called “fate determination”)?  Development is regulated by genetic programs that dictate a cell’s behavior.  Cells are not alone, but communicate with each other, affecting the genetic programs of their neighbors.  Thus, development is regulated within (intrinsic/autonomous) and between cells (extrinsic/non-autonomous).  Discovering how these genetic programs are regulated can explain development.  For example, knowing the molecular steps that drive the formation of cones may allow researchers to directly generate cone photoreceptors from stem cells, which could then be used to restore vision in patients with retinal disease.


We are interested in uncovering the mechanisms that regulate mammalian retinal development and applying this knowledge to inform novel treatments to restore vision.  We use the mouse as a model system, as its development is similar to human (Figure 3), and because there is a wealth of genetic resources we can utilize.  In particular, we are interested in three areas.

1.  Mechanisms of Cell Fate Determination:

How does a seemingly homogeneous population of retinal progenitor cells diversify into the myriad cell types in the retina?  These cells must choose between multiple possible cell fate outcomes at any given time in development.  What are the molecules that regulate fate choice?  We are currently investigating transcription factors (genes that regulate other genes) for their role in retinal development.  One factor of interest is Blimp1 (Prdm1).  This zinc finger transcription factor is expressed transiently in the retina and is important for the choice between photoreceptors and bipolar cells (Figure 4).  When Blimp1 is deleted, supernumerary bipolar cells form at the expense of photoreceptors (Figure 4).  This phenotype is not caused by a failure of photoreceptors to form, but instead, photoreceptor identity is lost and superseded by bipolar identity.  We are currently investigating the mechanisms by which Blimp1 stabilizes photoreceptor fate choice and the molecules that promote bipolar cell identity.

2. Gene Regulatory Networks:

Transcription factors bind to DNA regulatory sequences around or within genes, where they can activate or repress expression of a gene.  Transcription factors play a critical role in regulating retinal development, but little is known about the positive (enhancer) and negative (silencer) regulatory sequences that are important.  It is often difficult to determine what is upstream of a given gene.  By carefully examining regulatory elements of key retinal transcription factors, we can identify upstream factors and thus the earliest events in the cell fate choice cascade.  Currently, we are examining the regulatory factors that drive Blimp1 and other genes in the retina (Figure 5).  We are also interested in characterizing silencing elements, which are vital for proper development.

3. Cell-Cell Interactions and Vascular Development:

Cells are able to influence the development of other cells.  It is common for one group of cells to regulate the size, fate, and/or timing of other cell populations during development.  For example, RGCs are thought to inhibit their own production from progenitors as development proceeds (negative feedback).  Within the retina, there are other cell types that have separate developmental origins.  Retinal astrocytes and vascular cells originate outside the eye and colonize the retina relatively late in development (Figure 1).  Mice lacking the transcription factor Math5 are deficient for RGCs.  Interestingly, these mice also have abnormalities in astrocytes and the retinal vasculature (Figure 6).  People with mutations in MATH5 (also called ATOH7) also have RGC and vascular defects.  Math5 is not expressed in astrocytes or vascular cells, so RGCs themselves influence the development of these cell types.  We are currently investigating how RGCs affect the development of retinal astrocytes and the vasculature.  Understanding these early developmental events may help design treatments for retinal vascular disorders, such as diabetic retinopathy or persistent hyperplastic primary vitreous (PHPV). 

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Principal Investigator

Brz 200.jpgJoe Brzezinski, Ph.D.
Assistant Professor
E-Mail

 

Joe grew up in the Niagara Falls region of upstate New York.  He went to college at SUNY Fredonia and got a B.S. in Recombinant Gene Technology.  In 1999, he went to the University of Michigan for Graduate School.  Joe studied retinal development with Dr. Tom Glaser in the Department of Human Genetics.  In 2006, he went to Northwestern to study cortical development with Dr. Anjen Chenn.  In 2007, he joined Dr. Tom Reh’s lab at the University of Washington.  There, he continued his studies of retinal development.  Joe joined the Department of Ophthalmology at the University of Colorado Denver in 2012.

 

  

 
Laboratory Staff

Ko.jpgKo Uoon Park, M.S.
Laboratory Manager
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Ko was born in Seoul, South Korea and came to the United States in 2003 to study biology.  She graduated with a B.A. degree in Molecular Cellular and Developmental Biology from the University of Colorado Boulder.  Ko then went to the University of Southern California, where she studied with Dr. James Ou.  She obtained her M.S in Molecular Microbiology and Immunology in 2010.  Her thesis was on, “The effect of cofilin on Hepatitis C virus (HCV) core protein association with lipid droplet (LD) and LD redistribution in HDV infected cells”.  Ko joined the lab as a Professional Research Assistant in 2012. 

 

 

Peer Reviewed Publications

  1. Brown NL, Patel S, Brzezinski J, Glaser T. (2001) Math5 is required for retinal ganglion cell and optic nerve formation. Development, 128(13):2497-508.  PMID: 11493566.
  2. Brzezinski JA, Brown NL, Tanikawa A, Bush RA, Sieving PA, Vitaterna MH, Takahashi JS, Glaser T. (2005) Loss of circadian photoentrainment and abnormal retinal electrophysiology in Math5 mutant mice. Invest Ophthalmol Vis Sci, 46(7):2540-51.  PMID: 15980246.
  3. Akimoto M, Cheng H, Zhu D, Brzezinski JA, Khanna R, Filippova E, Oh EC, Jing Y, Linares JL, Brooks M, Zareparsi S, Mears AJ, Hero A, Glaser T, Swaroop A. (2006) From the Cover: Targeting of GFP to newborn rods by Nrl promoter and temporal expression profiling of flow-sorted photoreceptors. Proc Natl Acad Sci U S A, 103(10):3890-5.  PMID: 16505381.
  4. Saul SM, Brzezinski JA, Altshuler RA, Shore SE, Rudolph D, Kabara, LL, Halsey KE, Hufnagel RB, Zhou J, Dolan DF, Glaser T.  (2008) Math5 expression and function in the central auditory system.  Mol Cell Neurosci, 37(1):153-169.  PMID: 17977745.
  5. Brzezinski JA, Lamba DA, and Reh TA.  (2010) Blimp1 controls photoreceptor versus bipolar cell fate choice during retinal development.  Development, 137:619-629.  PMID: 20110327.
  6. Ghiasvand NM, Rudolph DR, Mashayekhi M, Brzezinski JA, Goldman DJ and Glaser T. (2011) Deletion of a remote enhancer controlling ATOH7 bHLH gene expression disrupts retinal neurogenesis, causing congenital nonattachment.  Nature Neuroscience, 14:578-86.  PMID: 21441919.
  7. Brzezinski JA, Kim EJ, Johnson JE, and Reh TA. (2011) Ascl1 defines a subpopulation of lineage-restricted progenitors in the mammalian retina.  Development, 138:3519-31.  PMID: 21771810.
  8. Brzezinski JA, Prasov L, and Glaser T.  (2012) Math5 defines the ganglion cell competence state in a subpopulation of retinal progenitor cells exiting the cell cycle. Dev Biol, 365:395-413.  PMID: 22445509.

Book Chapters

  1. Brzezinski, JA and Reh, TA. (2010) Retinal Histogenesis. In Encyclopedia of the eye (ed. Dartt, DA, Besharse JC, and Dana, R). Boston, MA: Elsevier.