David Howard's Research Page
As of 2011, my research interests have expanded beyond cilia
and flagella. My lab has established numerous collaborations with other
research labs in La Crosse.
Newer research projects include:
Cold-induced changes in organization of
microtubules in platelets from hibernating ground squirrels
Hibernation-induced changes in ground squirrel
Effects of toxins that act as endocrine mimics
on fish sperm motility
Gill structure and filter
feeding in invasive asian carp
Much of the information below on my work with
Chlamydomonas and flagella has not been recently updated.
Overview of Research Interests
Research in my lab investigates how organisms generate and
control movement at the cellular and molecular levels. This area of
biology is called cell motility and the cytoskeleton. Most of my
work is focused on understanding what controls the speed and strength of beating
in cilia and flagella. Cilia and flagella are long, thin organelles that
extend from eukaryotic cells. Cilia and flagella beat by propagating bends
down their length. This beating is cartooned in the animation below.
||The single-celled green alga
has two flagella which beat to cause the cell to swim through liquid.
The Chlamydomonas in the cartoon would be swimming toward the top of
the screen. The beating has been slowed down about 50X so that you can
see a full beat cycle. Ordinarily, the flagella beat too fast for the
eye to see.
the Chlamy Center)
Widespread Importance of Cilia & Flagella
Virtually all animals, many protists, and all lower plants
(mosses and ferns) possess cilia &/or flagella and use them for one or more
vital functions. Common examples of cilia and flagella include the sperm
tails of swimming sperm, the respiratory cilia which clean out the respiratory
tract in mammals, and oviductal cilia which help move the egg down the Fallopian
tubes in mammals. (Visit the
Talbot Lab to see
movies of this in action.)
Cilia and Flagella in Human Health
Numerous human diseases are caused by defective cilia
and/or flagella. Some of these diseases include:
- Developmental defects that cause internal organs to be
misplaced or malformed (primary ciliary dyskinesia 1/20,000 births1, Kartagener
syndrome1, and lateralization defects 1/8,000 births3)
- A disease that results in numerous cysts developing in
the kidneys which damage the kidneys (polycystic kidney disease at 1/10,000
- Degeneration of the retina and loss of sight in
diseases like retinitis pigmentosa10,12
- Bardet-Biedl syndrome, a relatively rare disorder
associated with a variety of health problems including retinal degeneration,
obesity, kidney malformations, polydactyly, and learning disabilities.2,9
- Defects in brain development (hydrocephalus)8
- Male infertility due to immotile or poorly motile sperm1,7
- Reduced female fertility due to immotile oviductal cilia1
In addition to these diseases, recent evidence indicates
that primary cilia are the strain sensors in bone cells called osteocytes14.
Thus, cilia may also be important in controlling bone density and osteoporosis.
Current and Recent Research Focus
Numerous lines of evidence indicate that the enzyme
cAMP-dependent protein kinase (PKA) is involved in the regulation of
flagellar beating. As a kinase, this PKA enzyme should exert its effects
by phosphorylating one or more proteins to turn these proteins on or off.
However, the targets of PKA are not known for most cilia and flagella, including
those of humans. Although we are interested in all aspects of flagellar
beating, most recent efforts in my lab have been focused on studying
|For most of our work, we use the model
organism Chlamydomonas to study flagellar PKA and the control of
flagellar beating5. Chlamydomonas is the most powerful
model system for studying cilia and flagella, and much of the recent
progress in understanding human diseases related to cilia and flagella comes
from studying this organism3,7,13.
Go to our Chlamydomonas research page to find
out what's going on now.
|In sperm flagella, PKA often acts to
initially activate beating of the flagella and thus swimming of the sperm.
Colleen Trantow6 (an undergraduate in my lab) recently investigated
PKA in the sperm from the Asian clam Corbicula fluminea.
Corbicula sperm are highly unusual because they possess two flagella
(indicated by the A and B in the figure to the left) instead of one.
We found that PKA activates both flagella in Corbicula.
Furthermore, Colleen found that the related enzyme PKG also activates
motility. This was the first clear case of both PKA and PKG activating sperm
BA, Mossberg B, & Bergstrom SE. 2001. Immotile cilia syndrome (primary
ciliary dyskinesia), including Kartagener syndrome. in The Metabolic and
Molecular Bases of Inherited Disease, eds. Scriver, C. R., Beaudet, A. L.,
Sly, W. S. & Valle, D. (McGraw–Hill, New York), pp. 4817–27.
Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, Kim JC, Ross AJ, Eichers
ER, Teslovich TM, Mah AK, Johnsen RC, Cavender JC, Lewis RA, Leroux MR, Beales
PL, Katsanis N. 2003. Basal body dysfunction is a likely cause of pleiotropic
Bardet-Biedl syndrome. Nature. 425:628-33.
El Zein L,
Omran H, Bouvagnet P. 2003. Lateralization defects and ciliary dyskinesia:
lessons from algae. Trends Genet. 19:162-7.
N, Takemura R. 2003. Biochemical and molecular characterization of diseases
linked to motor proteins. Trends Biochem Sci. 28:558-65.
DR, Habermacher G, Glass DB, Smith EF, Sale WS.
1994. Regulation of Chlamydomonas flagellar dynein by an axonemal protein
kinase. J Cell Biol 127:1683-92.
Howard, D.R., C.M. Trantow, and C.D. Thaler. 2004.
Motility of a biflagellate sperm: Waveform analysis and cyclic nucleotide
activation. Cell Motil. Cytoskel. 59:120-130.
I, Heintz N, Omran H. 2003. To beat or not to beat: roles of cilia in
development and disease. Hum Mol Genet. 12 Spec No 1:R27-35.
Ibanez-Tallon I, Pagenstecher
A, Fliegauf M, Olbrich H, Kispert A, Ketelsen UP, North A, Heintz N, Omran H.
2004. Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits
ependymal flow and reveals a novel mechanism for hydrocephalus formation.
Hum Mol Genet. 13:2133-41.
Gerdes JM, Haycraft CJ, Fan Y, Teslovich TM, May-Simera H, Li H, Blacque OE,
Li L, Leitch CC, Lewis RA, Green JS, Parfrey PS, Leroux MR, Davidson WS,
Beales PL, Guay-Woodford LM, Yoder BK, Stormo GD, Katsanis N, Dutcher SK.
2004. Comparative genomics identifies a flagellar and basal body proteome that
includes the BBS5 human disease gene. Cell. 117:541-52.
JR, Liu X, Roberts EA, Chui D, Marth JD, Williams DS, Goldstein LS.
2000.Genetic evidence for selective transport of opsin and arrestin by
kinesin-II in mammalian photoreceptors. Cell. 102:175-87.
Dickert BL, Vucica Y, Seeley ES, Rosenbaum JL, Witman GB, Cole DG. 2000.
Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene
tg737, are required for assembly of cilia and flagella. J Cell Biol.151:709-18.
Baker SA, Deane JA, Cole DG, Dickert BL, Rosenbaum JL, Witman GB, Besharse JC.
2002. The intraflagellar transport protein, IFT88, is essential for vertebrate
photoreceptor assembly and maintenance. J Cell Biol. 157:103-13.
Pan J, Wang Q. 2004. Cilia and flagella revealed: from flagellar assembly in
Chlamydomonas to human obesity disorders. Cell. 117:693-7.
Whitfield JF. 2003.
Primary cilium--is it an osteocyte's strain-sensing flowmeter? J Cell
This is not an exhaustive list of the literature in this area, but merely a place for the interested to start learning.
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