Cdx4 regulates onset of spinal cord neurogenesis.

Piyush Joshi, Isaac Skromne

Spinal cord neurogenesis at the caudal most end of the vertebrate embryo critically depends on
the balance of two processes: primordial cell proliferation and differentiation. The caudal neural
plate has a limited number of stem cell that self-renew while giving rise to the entire spinal cord
via continuous generation of neural cell progenitors. Changes in the rate of cell-renewal and
differentiation can result in spinal cord malformations with compromised function. While the
molecular components driving spinal cord stem cell proliferation and differentiation are being
elucidated, the molecular components driving the proliferation to differentiation switch are
poorly understood.
Here we show that Cdx4, a transcription factor essential for neural tube anteroposterior
patterning, regulates the proliferation to differentiation switch in spinal cord neural primordial
cells. In gain and loss of function experiments in chicks, we show that Cdx4 functions as a
differentiation switch by activating neurogenic factor Pax6 while repressing the pluripotency
factor Cash4. Bioinformatics analysis supports a direct regulation of Pax6 by Cdx4, as Pax6 has
two clusters of Cdx4 binding sites that are evolutionarily conserved among vertebrates.
Moreover we also show that Cdx4 regulate the Notch signaling in the transition zone of the
spinal cord by inhibiting Hes5 expression, indicating that Cdx4 regulates other differentiation
genes. Together our findings suggest that, in addition to its previous known role in pattering,
Cdx have a key function in regulating onset of spinal cord neurogenesis.

Funding:
UM Dept. of Biology Kushlan fund. 2013-14
UM College of Arts and Sciences Graduate Summer Research Fellowship, 2014
Sigma XI GIAR, 2014