Prdm13 Mediates the Balance of Inhibitory and Excitatory Neurons in Somatosensory Circuits

Chang, Joshua C.; Meredith, David M.; Mayer, Paul R.; Borromeo, Mark D.; Lai, Helen C.; Ou, Yi-Hung; Johnson, Jane E.

doi:10.1016/j.devcel.2013.02.015

Cited by 60 publications

(126 citation statements)

References 56 publications

(107 reference statements)

Supporting

Mentioning

116

Contrasting

Unclassified

Order By: Relevance

“…Genomic regions containing the Ptf1a sites near Lhx1 and Pax2, and the Ascl1 binding site near Tlx3 (Fig. 4B,C, peaks highlighted in beige), drive reporter activity in the dorsal neural tube in transgenic animals (Chang et al, 2013;Meredith et al, 2013), thereby validating their function.…”

Section: Ascl1 and Ptf1a Have Opposite Actions In Neuronal Subtype Spmentioning

confidence: 84%

“…3E) (Mizuguchi et al, 2006). There are additional complexities and feedback loops in the transcriptional network, including repressive interactions of Tlx1/3 on Pax2 levels (Cheng et al, 2005), and involvement of other TFs, such as Prdm13 (Chang et al, 2013) (see diagram Fig. 1C).…”

Section: Ascl1 and Ptf1a Have Opposite Actions In Neuronal Subtype Spmentioning

confidence: 99%

“…The high number of repressed genes predicted in this analysis was unexpected, as Ascl1 and Ptf1a are primarily known as transcriptional activators. (Chang et al, 2013;Meredith et al, 2013). (B 0 ,C 0 ) ChIP-qPCR validating several Ptf1a-and Ascl1-binding sites found in the ChIP-Seq assay.…”

Section: Ascl1 and Ptf1a Have Opposite Actions In Neuronal Subtype Spmentioning

confidence: 99%

“…For example, loss of Ptf1a results in a loss of GABAergic neurons and excess glutamatergic neurons in the spinal cord dorsal horn (Glasgow et al, 2005). By contrast, Ascl1 has the opposite effect and is necessary and sufficient for generation of early-born glutamatergic neurons (Chang et al, 2013;Helms et al, 2005;Mizuguchi et al, 2006;Nakada et al, 2004). Robust disruption in HD factor expression is reported as a primary phenotype in Ascl1 and Ptf1a mutants.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A transcription factor network specifying inhibitory versus excitatory neurons in the dorsal spinal cord

et al. 2014

View full text Add to dashboard Cite

The proper balance of excitatory and inhibitory neurons is crucial for normal processing of somatosensory information in the dorsal spinal cord. Two neural basic helix-loop-helix transcription factors (TFs), Ascl1 and Ptf1a, have contrasting functions in specifying these neurons. To understand how Ascl1 and Ptf1a function in this process, we identified their direct transcriptional targets genome-wide in the embryonic mouse neural tube using ChIP-Seq and RNA-Seq. We show that Ascl1 and Ptf1a directly regulate distinct homeodomain TFs that specify excitatory or inhibitory neuronal fates. In addition, Ascl1 directly regulates genes with roles in several steps of the neurogenic program, including Notch signaling, neuronal differentiation, axon guidance and synapse formation. By contrast, Ptf1a directly regulates genes encoding components of the neurotransmitter machinery in inhibitory neurons, and other later aspects of neural development distinct from those regulated by Ascl1. Moreover, Ptf1a represses the excitatory neuronal fate by directly repressing several targets of Ascl1. Ascl1 and Ptf1a bind sequences primarily enriched for a specific E-Box motif (CAGCTG) and for secondary motifs used by Sox, Rfx, Pou and homeodomain factors. Ptf1a also binds sequences uniquely enriched in the CAGATG E-box and in the binding motif for its co-factor Rbpj, providing two factors that influence the specificity of Ptf1a binding. The direct transcriptional targets identified for Ascl1 and Ptf1a provide a molecular understanding of how these DNA-binding proteins function in neuronal development, particularly as key regulators of homeodomain TFs required for neuronal subtype specification.National Institutes of Health grants: ([F31NS705592, R01 HD037932, R01 NS032817, F31 NS06144

show abstract

Section: Ascl1 and Ptf1a Have Opposite Actions In Neuronal Subtype Spmentioning

confidence: 84%

Section: Ascl1 and Ptf1a Have Opposite Actions In Neuronal Subtype Spmentioning

confidence: 99%

Section: Ascl1 and Ptf1a Have Opposite Actions In Neuronal Subtype Spmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A transcription factor network specifying inhibitory versus excitatory neurons in the dorsal spinal cord

et al. 2014

View full text Add to dashboard Cite

show abstract

“…2H,I). Comparing Prdm12 and Prdm13 expressed in dp2-dp6 (Chang et al, 2013), this expansion appears limited to the p0 domain, which is defective in Dbx1 lacZ/lacZ embryos (supplementary material Fig. S10).…”

Section: Cloning and Expression Of Xenopus Chicken And Amphioxus Prdmentioning

confidence: 99%

Prdm12 specifies V1 interneurons through cross-repressive interactions with Dbx1 and Nkx6 genes in Xenopus

et al. 2015

View full text Add to dashboard Cite

V1 interneurons are inhibitory neurons that play an essential role in vertebrate locomotion. The molecular mechanisms underlying their genesis remain, however, largely undefined. Here, we show that the transcription factor Prdm12 is selectively expressed in p1 progenitors of the hindbrain and spinal cord in the frog embryo, and that a similar restricted expression profile is observed in the nerve cord of other vertebrates as well as of the cephalochordate amphioxus. Using frog, chick and mice, we analyzed the regulation of Prdm12 and found that its expression in the caudal neural tube is dependent on retinoic acid and Pax6, and that it is restricted to p1 progenitors, due to the repressive action of Dbx1 and Nkx6-1/2 expressed in the adjacent p0 and p2 domains. Functional studies in the frog, including genomewide identification of its targets by RNA-seq and ChIP-Seq, reveal that vertebrate Prdm12 proteins act as a general determinant of V1 cell fate, at least in part, by directly repressing Dbx1 and Nkx6 genes. This probably occurs by recruiting the methyltransferase G9a, an activity that is not displayed by the amphioxus Prdm12 protein. Together, these findings indicate that Prdm12 promotes V1 interneurons through cross-repressive interactions with Dbx1 and Nkx6 genes, and suggest that this function might have only been acquired after the split of the vertebrate and cephalochordate lineages.

show abstract

Unique noncoding variants upstream of PRDM13 are associated with a spectrum of developmental retinal dystrophies including progressive bifocal chorioretinal atrophy

et al. 2019

View full text Add to dashboard Cite

The autosomal dominant progressive bifocal chorioretinal atrophy (PBCRA) disease locus has been mapped to chromosome 6q14-16.2 that overlaps the North Carolina macular dystrophy (NCMD) locus MCDR1. NCMD is a nonprogressive developmental macular dystrophy, in which variants upstream of PRDM13 have been implicated. Whole genome sequencing was performed to interrogate structural variants (SVs) and single nucleotide variants (SNVs) in eight individuals, six affected individuals from two families with PBCRA, and two individuals from an additional family with a related developmental macular dystrophy. A SNV (chr6:100,046,804T>C), located 7.8 kb upstream of the PRDM13 gene, was shared by all PBCRA-affected individuals in the disease locus. Haplotype analysis suggested that the variant arose independently in the two families. The two affected individuals from Family 3 were screened for rare variants in the PBCRA and NCMD loci. This revealed a de novo variant in the proband, 21 bp from the first SNV (chr6:100,046,783A>C). This study expands the Human Mutation. 2019;40:578-587. wileyonlinelibrary.com/journal/humu 578 |

show abstract

Prdm13 Mediates the Balance of Inhibitory and Excitatory Neurons in Somatosensory Circuits

Cited by 60 publications

References 56 publications

A transcription factor network specifying inhibitory versus excitatory neurons in the dorsal spinal cord

A transcription factor network specifying inhibitory versus excitatory neurons in the dorsal spinal cord

Prdm12 specifies V1 interneurons through cross-repressive interactions with Dbx1 and Nkx6 genes in Xenopus

Unique noncoding variants upstream of PRDM13 are associated with a spectrum of developmental retinal dystrophies including progressive bifocal chorioretinal atrophy

Contact Info

Product

Resources

About