The transcription factors Nkx2.2 and Nkx2.9 play a novel role in floor plate development and commissural axon guidance

TY - JOUR

T1 - The transcription factors Nkx2.2 and Nkx2.9 play a novel role in floor plate development and commissural axon guidance

AU - Holz, Andreas

AU - Kollmus, Heike

AU - Ryge, Jesper

AU - Niederkofler, Vera

AU - Dias, Jose

AU - Ericson, Johan

AU - Stoeckli, Esther T.

AU - Kiehn, Ole

AU - Arnold, Hans Henning

PY - 2010/12/15

Y1 - 2010/12/15

N2 - The transcription factors Nkx2.2 and Nkx2.9 have been proposed to execute partially overlapping functions in neuronal patterning of the ventral spinal cord in response to graded sonic hedgehog signaling. The present report shows that in mice lacking both Nkx2 proteins, the presumptive progenitor cells in the p3 domain of the neural tube convert to motor neurons (MN) and never acquire the fate of V3 interneurons. This result supports the concept that Nkx2 transcription factors are required to establish V3 progenitor cells by repressing the early MN lineage-specific program, including genes like Olig2. Nkx2.2 and Nkx2.9 proteins also perform an additional, hitherto unknown, function in the development of non-neuronal floor plate cells. Here, we demonstrate that loss of both Nkx2 genes results in an anatomically smaller and functionally impaired floor plate causing severe defects in axonal pathfinding of commissural neurons. Defective floor plates were also seen in Nkx2.2 +/-;Nkx2.9 -/- compound mutants and even in single Nkx2.9 -/- mutants, suggesting that floor plate development is sensitive to dose and/or timing of Nkx2 expression. Interestingly, adult Nkx2.2 +/-;Nkx2.9 -/- compound-mutant mice exhibit abnormal locomotion, including a permanent or intermittent hopping gait. Drug-induced locomotor-like activity in spinal cords of mutant neonates is also affected, demonstrating increased variability of left-right and flexor-extensor coordination. Our data argue that the Nkx2.2 and Nkx2.9 transcription factors contribute crucially to the formation of neuronal networks that function as central pattern generators for locomotor activity in the spinal cord. As both factors affect floor plate development, control of commissural axon trajectories might be the underlying mechanism.

AB - The transcription factors Nkx2.2 and Nkx2.9 have been proposed to execute partially overlapping functions in neuronal patterning of the ventral spinal cord in response to graded sonic hedgehog signaling. The present report shows that in mice lacking both Nkx2 proteins, the presumptive progenitor cells in the p3 domain of the neural tube convert to motor neurons (MN) and never acquire the fate of V3 interneurons. This result supports the concept that Nkx2 transcription factors are required to establish V3 progenitor cells by repressing the early MN lineage-specific program, including genes like Olig2. Nkx2.2 and Nkx2.9 proteins also perform an additional, hitherto unknown, function in the development of non-neuronal floor plate cells. Here, we demonstrate that loss of both Nkx2 genes results in an anatomically smaller and functionally impaired floor plate causing severe defects in axonal pathfinding of commissural neurons. Defective floor plates were also seen in Nkx2.2 +/-;Nkx2.9 -/- compound mutants and even in single Nkx2.9 -/- mutants, suggesting that floor plate development is sensitive to dose and/or timing of Nkx2 expression. Interestingly, adult Nkx2.2 +/-;Nkx2.9 -/- compound-mutant mice exhibit abnormal locomotion, including a permanent or intermittent hopping gait. Drug-induced locomotor-like activity in spinal cords of mutant neonates is also affected, demonstrating increased variability of left-right and flexor-extensor coordination. Our data argue that the Nkx2.2 and Nkx2.9 transcription factors contribute crucially to the formation of neuronal networks that function as central pattern generators for locomotor activity in the spinal cord. As both factors affect floor plate development, control of commissural axon trajectories might be the underlying mechanism.

KW - Central pattern generators in spinal cord

KW - Floor plate development

KW - Mouse

KW - Nkx2.2

KW - Nkx2.9

UR - http://www.scopus.com/inward/record.url?scp=78650207853&partnerID=8YFLogxK

U2 - 10.1242/dev.053819

DO - 10.1242/dev.053819

M3 - Journal article

C2 - 21068056

AN - SCOPUS:78650207853

SN - 0950-1991

VL - 137

SP - 4249

EP - 4260

JO - Development

JF - Development

IS - 24

ER -