Global control of motor neuron topography mediated by the repressive actions of a single hox gene.
In the developing spinal cord, regional and combinatorial activities of Hox transcription factors are critical in controlling motor neuron fates along the rostrocaudal axis, exemplified by the precise pattern of limb innervation by more than fifty Hox-dependent motor pools. The mechanisms by which motor neuron diversity is constrained to limb levels are, however, not well understood. We show that a single Hox gene, Hoxc9, has an essential role in organizing the motor system through global repressive activities. Hoxc9 is required for the generation of thoracic motor columns, and in its absence, neurons acquire the fates of limb-innervating populations. Unexpectedly, multiple Hox genes are derepressed in Hoxc9 mutants, leading to motor pool disorganization and alterations in the connections by thoracic and forelimb-level subtypes. Genome-wide analysis of Hoxc9 binding suggests that this mode of repression is mediated by direct interactions with Hox regulatory elements, independent of chromatin marks typically associated with repressed Hox genes.
Jung
Heekyung
H
Howard Hughes Medical Institute, Smilow Neuroscience Program, Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016, USA.
Lacombe
Julie
J
Mazzoni
Esteban O
EO
Liem
Karel F
KF
Grinstein
Jonathan
J
Mahony
Shaun
S
Mukhopadhyay
Debnath
D
Gifford
David K
DK
Young
Richard A
RA
Anderson
Kathryn V
KV
Wichterle
Hynek
H
Dasen
Jeremy S
JS
D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism; D002642:Chick Embryo; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004252:DNA Mutational Analysis; D018274:Electroporation / Q000379:methods; D005121:Extremities / Q000254:growth & development / Q000294:innervation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012445:Sacrococcygeal Region; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology* / Q000254:growth & development
D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; D018398:Homeodomain Proteins; C065404:Hoxc9 protein, mouse; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D049452:Green Fluorescent Proteins; D052248:Nitric Oxide Synthase Type I; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse
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