First name
Ganesh
Last name
Bhat
Year of Study
Research Center
Thesis Title
Sox17 is a co-effector in Wnt/β-catenin mediated blood-brain barrier development and maintenance
Thesis Abstract
The presence of blood-brain barrier (BBB) at the level of endothelial cells (ECs) that
line the capillaries in the brain is a challenge while treating intracranial tumors or
many neurological disorders since BBB could block the passage of many solvents or
drugs entering from systemic circulation to brain parenchyma. Researchers are trying
to understand how BBB is induced during development and maintained in adult life
in order to develop new tools to enhance drug delivery across BBB. Many signaling
pathway that are active during BBB development are unraveled through mainly
reverse genetic approach and gene knock out studies. Wnt/β-catenin signaling well
known for its role in organ development, morphogenesis and in cancer causation is
also reported to be essential for BBB induction and maintenance in most vertebrates.
However many target molecules or effectors of this pathway remain to be identified.
Previously we have identified Sox17 a SoxF family transcription factor, as a
downstream molecule of Wnt/β-catenin signaling. It plays a key role in arterial
differentiation of the vasculature of different organs. We found that Sox17 is also
expressed at high levels in brain ECs throughout embryo development and in the
adult vasculature. EC-specific gain of function of β-catenin (GOF) increases Sox17
expression in BBB ECs and may induce ectopic expression of Sox17 also in the
choroid plexus vasculature that lacks the BBB.
We hypothesized therefore that Sox17 might be involved in BBB development and
maintenance downstream to the Wnt pathway. In Sox17 null mice we analyzed
different functional characteristics of BBB such as permeability control and specific
markers expression. The absence of this transcription factor leads to increase in BBB
permeability to high molecular weight molecules and marked increase in PLVAP, a
protein inversely related to maturation of BBB. We also observed significant
reduction in the β-catenin signaling itself by employing BAT-gal reporter in Sox17
15
null background. In addition, many direct β-catenin targets like Axin2 and LEF1
were decreased upon Sox17 abrogation. These data suggested that Sox17 is not only
a target of β-catenin signaling but also could maintain steady state, detectable levels
of β-catenin signaling. We could rescue β-catenin signaling and correct BBB defects
by either inhibiting the β-catenin destruction complex or by employing GOF β-
catenin in Sox17 null background. Our study shows that Sox17 is an important
regulator of BBB and it partially acts by sustaining β-catenin signaling. Sox17
expression and signaling may be important in pathological conditions like
intracranial tumors and modulation of its activity could have clinical implications
and therapeutic benefits.
line the capillaries in the brain is a challenge while treating intracranial tumors or
many neurological disorders since BBB could block the passage of many solvents or
drugs entering from systemic circulation to brain parenchyma. Researchers are trying
to understand how BBB is induced during development and maintained in adult life
in order to develop new tools to enhance drug delivery across BBB. Many signaling
pathway that are active during BBB development are unraveled through mainly
reverse genetic approach and gene knock out studies. Wnt/β-catenin signaling well
known for its role in organ development, morphogenesis and in cancer causation is
also reported to be essential for BBB induction and maintenance in most vertebrates.
However many target molecules or effectors of this pathway remain to be identified.
Previously we have identified Sox17 a SoxF family transcription factor, as a
downstream molecule of Wnt/β-catenin signaling. It plays a key role in arterial
differentiation of the vasculature of different organs. We found that Sox17 is also
expressed at high levels in brain ECs throughout embryo development and in the
adult vasculature. EC-specific gain of function of β-catenin (GOF) increases Sox17
expression in BBB ECs and may induce ectopic expression of Sox17 also in the
choroid plexus vasculature that lacks the BBB.
We hypothesized therefore that Sox17 might be involved in BBB development and
maintenance downstream to the Wnt pathway. In Sox17 null mice we analyzed
different functional characteristics of BBB such as permeability control and specific
markers expression. The absence of this transcription factor leads to increase in BBB
permeability to high molecular weight molecules and marked increase in PLVAP, a
protein inversely related to maturation of BBB. We also observed significant
reduction in the β-catenin signaling itself by employing BAT-gal reporter in Sox17
15
null background. In addition, many direct β-catenin targets like Axin2 and LEF1
were decreased upon Sox17 abrogation. These data suggested that Sox17 is not only
a target of β-catenin signaling but also could maintain steady state, detectable levels
of β-catenin signaling. We could rescue β-catenin signaling and correct BBB defects
by either inhibiting the β-catenin destruction complex or by employing GOF β-
catenin in Sox17 null background. Our study shows that Sox17 is an important
regulator of BBB and it partially acts by sustaining β-catenin signaling. Sox17
expression and signaling may be important in pathological conditions like
intracranial tumors and modulation of its activity could have clinical implications
and therapeutic benefits.
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