|
Pattern formation and regeneration in mice and Xenopus
The overall aim of our research is to define the molecular basis of embryonic pattern formation. Pattern
formation is a process which leads to ordered spatial arrangements of differentiated tissues. It is not only interesting from
a theoretical standpoint, but from a medical perspective as well. Each year in USA alone more than 250,000 infants are born
with congenital malformation due to incorrect embryonic patterning. It is our goal to identify genes that are involved in
pattern formation and characterize developmental processes that lead to correct and incorrect pattern formation. The major
research effort in our laboratory is focused on study of homeobox and fork head genes that are involved in the patterning of
the embryo. We have identified several genes that are important in early stages of head development
We have found a novel homeobox gene Rx that is essential for normal eye development. Rx is initially
expressed in retinal progenitor cells and later in retinal stem cells. Xenopus embryos injected with Rx RNA
develop ectopic retinal tissue and display hyperproliferation in the neuroretina. Mouse embryos carrying a null allele of
this gene do not form optic cups and consequently do not develop eyes. These observations suggest that Rx regulates
the fate or the proliferative abilities of retinal cells and controls the survival of retinal stem cells (Mathers et
al., 1997).
We have isolated a Xenopus forkhead gene Xlens1 that is the earliest marker of lens formation and is
involved in the control of lens proliferation and differentiation (Kenyon et al., 1999). We have cloned and
characterized its murine functional homologue, the forkhead gene Foxe3 that is expressed in the early stages of mouse
lens formation. Foxe3, like Xlens1, is expressed in the initial stages of lens induction. It turns off its
expression in differentiating fiber cells and remains active only in the relatively undifferentiated, proliferative cells of
the anterior lens epithelium. Foxe3 maps to a region on chromosome 4 that contains the dysgenetic lens (dyl) locus.
We have found that two mutations in the forkhead box of the Foxe3 allele from dyl mice cause amino acid changes
in positions thought to be essential for the structure and function of winged helix domains (Brownell et al., 2000).
Furthermore, we have found that a mutation affecting C-terminal region of the human FOXE3 protein is responsible for
anterior segment dysgenesis and cataracts (Semina et al., 2001). We are currently testing gene therapy strategies that
would correct this genetic defect.
Selected Publications
Mathers P, Grinberg A, Mahon KA, Jamrich M (1997) The Rx homeobox gene is essential for
vertebrate eye development. Nature 387:603-607.
Kenyon KL, Moody SA, Jamrich M (1999) A novel fork head gene mediates early steps during
Xenopus lens formation. Development 126:5107-5116.
Brownell I, Dirksen M, Jamrich M (2000) Forkhead Foxe3 maps to the dysgenetic lens locus and is
critical in lens development and differentiation. Genesis 27:81-93.
Zhang L, Mathers PH, Jamrich M (2000) Function of Rx, but not Pax6, is essential for the
formation of retinal progenitor cells in mice. Genesis 28:135-142.
Semina EV, Brownell I, Mintz-Hittner HA, Murray JC, Jamrich M (2001) Mutations in the human forkhead
transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts. Human
Molecular Genetics 10:231-236.
Zhang L, El-Hodiri HM, Ma HF, Zhang X, Servetnick M, Wensel TG, Jamrich M (2003) Targeted expression of
the dominant-negative FGFR4a in the eye using Xrx1A regulatory sequences interferes with normal retinal development.
Development 130:4177-4186.
Tseng HT, Shah R, Jamrich M (2004) Function and regulation of FoxF1 during Xenopus gut development.
Development 131:3637-3647.
Wiszniewski W, Zaremba CM, Yatsenko AN, Jamrich M, Wensel TG, Lewis RA, Lupski JR (2005) ABCA4 mutations causing
mislocalization are found frequently in patients with severe retinal dystrophies. Human Molecular Genetics
14:2769-2778.
Medina-Martinez O, Brownell I, Amaya-Manzanares F, Hu Q, Behringer RR, Jamrich M (2005) Severe defects in proliferation
and differentiation of lens cells in Foxe3 null mice. Molecular and Cellular Biology 25:8854-8863.
Van Raay TJ, Moore KB, Iordanova I, Steele M, Jamrich M, Harris WA, Vetter ML (2005) Frizzled 5 signaling governs
the neural potential of progenitors in the developing Xenopus retina. Neuron 46:23-36.
Contact Information
- Milan Jamrich, Ph.D.
- Department of Molecular and Cellular Biology,
- Department of Molecular and Human Genetics
- Baylor College of Medicine
- One Baylor Plaza N620
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-3772
- Fax: (713) 798-3017
- E-mail: jamrich@bcm.tmc.edu
|
