ANNUAL REPORT - Department of Biotechnology

eleased from activated microglia are instrumental in
inducing neuronal death that accompanies JE.
These findings clearly suggest that microglial
activation may be an important contributory factor in
the pathogenesis of JE. In the central nervous
system (CNS) generation of phenotypic diversity
within the neuronal lineage is precisely regulated in a
spatial and temporal fashion. Neural basic helix-
loop- helix (bHLH) transcription factors are cell
intrinsic factors that control commitment to neuronal
lineage and play an important role in neuronal cell
type specification. The ability to differentiate human
embryonic stem (hES) cells into neurons provide a
good model system to address human neuronal
specification. Previous studies have shown
neurogenin 2 (Ngn2) to be involved in the
development of mesencephalic dopaminergic
neurons. Towards the goal of correlating neuronal
phenotype with early gene expression pattern, the
expression of Ngn2 has been characterized during
hES cell differentiation. The results show that
treatment of embryoid bodies (EB) with retinoic acid
(RA) leads to proportion of tyrosine hydroxylase (TH)
positive cells followed by vasoactive intestinal
peptide (VIP) treated EB and untreated EB. This
increase in the proportion of TH positive neurons was
correlated with the unique morphology of RA treated
aggregates and the spatial de-localization of the
expression of Ngn2 within the EB. Neurospheres
(NS) derived from RA treated EB contained many
nestin positive cells within regions that expressed
Ngn2. The data suggests that the appearance of TH
positive neurons is correlated with the extent of
overlap between Ngn2 expression and nestin
expression.
The molecular role of transcription factors in
photoreceptor differentiation and associated retinal
diseases was studied. The objective is to determine
the network of genes associated with the normal
photoreceptor development in retina. Neural Retina
Leucine zipper (NRL) is a key protein that regulates
expression of several photoreceptor specific genes
in retina. The mutations in NRL produce retinal
degeneration in affected patients. Y-Box binding
protein-1 (YB-1), a ubiquitously expressed
transcription factor interacts with NRL. Enhanced
expression of YB-1 represses NRL-mediated
transactivation of rhodopsin expression. This has
helped the identification of YB-1 as one of the few
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repressors known so far that affect NRL mediated
gene transcription in retina. Different mutations
associated with autosomal dominant retinitis
pigmentosa affect mitogen-activated protein kinasemediated
phosphorylation of NRL. Investigations of
the NRL-dependent molecular network and
influence of different signaling molecules in NRLspecific
gene regulation could unravel molecular
mechanism of photoreceptor differentiation and role
in associated retinopathies.
Systems & Computational Neuroscience: One of the
research programme aims to understand how the
sensorimotor system processes sensory information
to enable tactile perception and motor control, and
how spinal cord injuries in adult animals and during
early development affect functional organization of
the system. The motor areas of rats with unilateral
lesions of the dorsal columns at upper cervical levels
were mapped. The results showed that after injuries,
stimulation at many sites that were expected to relate
to the movement of the forearm, no movement of any
body part was evoked. However, at some of these
sites movements of the ipsilateral elbow and wrist
were evoked or there were bilateral movements. In
normal animals bilateral movements are elicited only
at a few points and that too only for the proximal
shoulder. Such reorganizations of the adult brain
following injuries can affect the outcome of the
rehabilitative therapies. The mechanisms of
emergence of distal ipsilateral movements following
lesions of the dorsal columns are currently under
investigation.
Transmission of visual information is disrupted in
retinal degenerative diseases such as Retinitis
Pigmentosa and Age-Related Macular
Degeneration, leading to blindness. Currently there
are no effective treatments for these diseases
because it is not clear how the complex retinal
circuitry develops, and how it processes visual
information. Investigations are on to study how
different types of retinal ganglion cells (RGCs)
receive, encode and transmit visual information to
the brain. The findings from these experiments would
have direct implications for developing therapeutic
retinal prostheses. In order to understand the mode
of action and control of health and disease has been
identified using saccadic eye movements as a model
system. The results reveals that the basis of such