Sabine P. Cordes, Ph. D.
600 University Avenue
(416) 586-8891
cordes@mshri.on.ca
Molecular Genetics of
Hindbrain Patterning and Serotonergic Neuron
Development
RESEARCH INTERESTS:
Vertebrate embryogenesis
Developmental Neurobiology
Hindbrain Patterning
Serotonergic neuron development
Mouse mutagenesis
Finely orchestrated and inter-related processes are responsible
for designing the vertebrate nervous system. Disruption of normal development
of the nervous system has been implicated in human disorders of mood and mind
and in some human cranio-facial syndromes.
Our laboratory is using molecular techniques and analysis of
pre-existing and newly generated mouse mutations to understand early neural
development, with particular focus on vertebrate hindbrain segmentation and serotonergic neuron development. Early in development the
vertebrate hindbrain is subdivided into 7-8 metameric
units, known as rhombomeres. How is exact positional
information specified within the neural tube?
Serotonergic neurons are born in
two main clusters in the ventral hindbrain. In humans disruption of hindbrain
patterning can result in craniofacial syndromes, while defects in serotonergic neurons and neurotransmission have been
implicated in some human disorders of mood and mind, such as depression,
schizophrenia, and anorexia nervosa. In animals interference with the serotonergic system can result in varying degrees of
hyperactivity, hyper-vocalization, abnormal aggression, and dysfunctional
eating behaviors. In humans all current anti-depressants act by inhibiting the
breakdown or re-uptake of serotonin, while some neuropharmaceuticals
used in the treatment of schizophrenia are serotonin antagonists.
Our current research activities on hindbrain patterning illustrate the power of mouse molecular genetics in providing novel molecular footholds for the study of neural development. Previously we cloned the gene affected by the kreisler (kr) mutation by its genetic map position 1. In kr/kr homozygotes a primary defect in hindbrain segmentation leads to abnormal differentiation of the otic vesicle and deafness and circling behavior in adult mice. The Kreisler gene encodes a novel basic domain leucine zipper (bZIP) transcription factor required for the development and segmentation of the posterior hindbrain, and regulates the expression of some Hox segmentation genes directly 2. Because the Kreisler protein regulates gene expression by forming protein complexes and is one of the earliest genes known to regulate vertebrate hindbrain patterning, we are using Kreisler as an entry point into understanding the mechanisms underlying early hindbrain segmentation and craniofacial development.
As another approach to study neuronal specification we are using
chemical mutagenesis and a series of streamlined assays to generate and
identify novel mouse mutations which affect serotonergic
neuron specification, differentiation, and neurotransmission. These novel mouse
mutations may help in the future understanding of some human disorders of mood
and mind and aid in the development of more efficacious pharmaceuticals for the
treatment of depression, schizophrenia, anorexia nervosa, and some other
neurological disorders, in which normal neuro-development
or neurotransmission have been disturbed.
Cordes, S. P. and G. S. Barsh
(1994) The mouse segmentation gene kreisler (kr) encodes a novel bzip
transcription factor. Cell 79, 1025-1034.
Manzanares, M., S.P.Cordes, C.-T. Kwan, M.-H Sham, G.Barsh,
and R.Krumlauf. (1997) Segmental regulation of Hoxb3
by Kreisler. Nature, 387, 191-195.
Moens, C.B., S.P.Cordes,
G.S. Barsh, and C. Kimmel. (1998) Equivalence of
hindbrain segmentation in the mouse and zebrafish. Development
125, 381-391.
Frohman, M.A., S.P. Cordes, L.P.
Halamek, G.S.Barsh and G.R.
Martin (1993) Altered rhombomere-specific gene
expression and hyoid bone differentiation in the mouse segmentation mutant, kreisler (kr). Development
117, 925-936.
Return to Department of Molecular Genetics Faculty Research Interests