ISL1-based LIM complexes control Slit2 transcription in developing cranial motor neurons.
LIM-homeodomain (HD) transcription factors form a multimeric complex and assign neuronal subtype identities, as demonstrated by the hexameric ISL1-LHX3 complex which gives rise to somatic motor (SM) neurons. However, the roles of combinatorial LIM code in motor neuron diversification and their subsequent differentiation is much less well understood. In the present study, we demonstrate that the ISL1 controls postmitotic cranial branchiomotor (BM) neurons including the positioning of the cell bodies and peripheral axon pathfinding. Unlike SM neurons, which transform into interneurons, BM neurons are normal in number and in marker expression in Isl1 mutant mice. Nevertheless, the movement of trigeminal and facial BM somata is stalled, and their peripheral axons are fewer or misrouted, with ectopic branches. Among genes whose expression level changes in previous ChIP-seq and microarray analyses in Isl1-deficient cell lines, we found that Slit2 transcript was almost absent from BM neurons of Isl1 mutants. Both ISL1-LHX3 and ISL1-LHX4 bound to the Slit2 enhancer and drove endogenous Slit2 expression in SM and BM neurons. Our findings suggest that combinations of ISL1 and LHX factors establish cell-type specificity and functional diversity in terms of motor neuron identities and/or axon development.
School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-gu, Gwangju 500-712, Republic of Korea.
Kyung-Tai
KT
Kim
School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-gu, Gwangju 500-712, Republic of Korea.
Namhee
N
Kim
Graduate School of Medicine, Korea University, Ansan 425-707, Korea.
Hwan-Ki
HK
Kim
School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-gu, Gwangju 500-712, Republic of Korea.
Hojae
H
Lee
Department of Biology, University of Nevada, Reno, NV 89557, USA.
Hannah N
HN
Gruner
Department of Human Genetics, University of Michigan, 1241 Catherine St, Ann Arbor, Michigan, MI-48109, USA.
Peter
P
Gergics
School of Biological Sciences and Technology, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 500-757, Republic of Korea.
Chungoo
C
Park
Department of Biology, University of Nevada, Reno, NV 89557, USA.
Grant S
GS
Mastick
Graduate School of Medicine, Korea University, Ansan 425-707, Korea.
Hae-Chul
HC
Park
School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-gu, Gwangju 500-712, Republic of Korea.
Mi-Ryoung
MR
Song
D000818:Animals; D001369:Axons / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007395:Interneurons / Q000502:physiology; D060850:LIM-Homeodomain Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D055495:Neurogenesis / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D066266:Trigeminal Motor Nucleus / Q000502:physiology; D000098552:Slit Homolog 2 Protein
D036341:Intercellular Signaling Peptides and Proteins; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1; D000098552:Slit Homolog 2 Protein