• Axons
• CDK13
• Craniofacial development
• Neurite outgrowth
• Orofacial clefts
• Trigeminal ganglion

• Animals
• Neurogenesis/genetics
• Disease Models, Animal
• Embryonic Development/genetics
• Gene Expression Regulation, Developmental
• Cyclin-Dependent Kinases/metabolism
• Cyclin-Dependent Kinases/genetics
• Skull/embryology
• Skull/pathology
• Mice
• Cleft Palate/genetics
• Cleft Palate/pathology
• Cleft Palate/embryology
• Cleft Lip/genetics
• Cleft Lip/pathology
• Cleft Lip/embryology
• Trigeminal Nerve/embryology
• Embryo, Mammalian/metabolism
• Face/embryology
• Face/abnormalities
• Phenotype
• Intellectual Disability/genetics
• Mutation/genetics
• Doublecortin Protein

• 19-01205S Czech Science Foundation
• 19-01205S Grantová Agentura České Republiky
• CZ.02.1.01/0.0/0.0/15_003/0000460 Ministerstvo Školství, Mládeže a Tělovýchovy

• Biological sciences
• Developmental neuroscience
• Natural sciences
• Neuroscience

• GLI transcription factors
• Hedgehog signaling
• congenital heart disease
• differentiation
• epigenetics
• gene regulatory network
• heart development
• heterochrony
• neuronal development
• progenitor

• Animals
• Cell Differentiation/genetics
• Gene Regulatory Networks
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Mice
• Signal Transduction/physiology
• Zinc Finger Protein GLI1/genetics

• F32 HL136168 NHLBI NIH HHS
• R01 HL124836 NHLBI NIH HHS
• R01 HL126509 NHLBI NIH HHS
• T32 HL007381 NHLBI NIH HHS
• R01 HL092153 NHLBI NIH HHS
• R01 HL147571 NHLBI NIH HHS
• T32 GM007183 NIGMS NIH HHS

Nociceptors in the dorsal root ganglia (DRG) and trigeminal ganglia (TG) are necessary for transmitting pain and itch signals. However, the molecular mechanism regulating nociceptor development remains largely unknown. This study identifies that the transcription factor Meis1 is generally expressed in two groups of sensory neurons in the developing DRG. During prenatal and neonatal stages, approximately 2/3 of Meis1+ neurons are Runx1+ nociceptors, while 1/3 of Meis1+ neurons are NF200+ myelinated neurons. At postnatal stages, Meis1 expression in nociceptors is gradually reduced. Here, we constructed a Meis1 conditional knockout mouse line to selectively delete Meis1 in Nav1.8 lineage nociceptors. Microarray analyses showed that differentially expressed genes in the Meis1 mutant DRG were enriched in pathways related to sensory perception of pain and nervous system development. In addition, Meis1 regulates the expression of some marker genes of Nppb+ neurons and C-LTMRs. Furthermore, Meis1 mutant mice exhibit behavioral deficits in response to light mechanical pain, static touch and chemical itch. Therefore, this study reveals that Meis1 is required to regulate the development of nociceptors.

• C-LTMR
• Meis1
• itch
• microarray
• nociceptor
• pain
• touch

The trigeminal column is a hindbrain structure formed by second order sensory neurons that receive afferences from trigeminal primary (ganglionic) nerve fibers. Classical studies subdivide it into the principal sensory trigeminal nucleus located next to the pontine nerve root, and the spinal trigeminal nucleus which in turn consists of oral, interpolar and caudal subnuclei. On the other hand, according to the prosomeric model, this column would be subdivided into segmental units derived from respective rhombomeres. Experimental studies have mapped the principal sensory trigeminal nucleus to pontine rhombomeres (r) r2-r3 in the mouse. The spinal trigeminal nucleus emerges as a plurisegmental formation covering several rhombomeres (r4 to r11 in mice) across pontine, retropontine and medullary hindbrain regions. In the present work we reexamined the issue of rhombomeric vs. classical subdivisions of this column. To this end, we analyzed its subdivisions in an AZIN2-lacZ transgenic mouse, known as a reference model for hindbrain topography, together with transgenic reporter lines for trigeminal fibers. We screened as well for genes differentially expressed along the axial dimension of this structure in the adult and juvenile mouse brain. This analysis yielded genes from multiple functional families that display transverse domains fitting the mentioned rhombomeric map. The spinal trigeminal nucleus thus represents a plurisegmental structure with a series of distinct neuromeric units having unique combinatorial molecular profiles.

• calcium-binding proteins
• fibronectin
• hindbrain
• rhombomeres
• somatosensory system
• tachykinins
• transcription factors
• trigeminal system

• Channelopathy
• Congenital insensitivity to pain
• Development
• Itch
• Neurotrophic factor signaling
• Pain
• Primary afferents
• Somatosensory neurons
• Transcriptional factors

• Humans
• Neurons
• Nociceptors
• Pain
• Pruritus

• F31 DE029361 NIDCR NIH HHS
• R01 NS083702 NINDS NIH HHS
• R01 NS094224 NINDS NIH HHS
• R34 NS118411 NINDS NIH HHS

• cranial sensory ganglia
• neural crest
• nociceptor
• placodes
• somatosensory neuron
• transcription factor
• visceral sensory neuron

• Brn3
• POU homeobox genes
• UNC-86
• neuronal identity
• terminal differentiation regulation

• Cell reprogramming
• Direct reprogramming
• GABAergic neurons
• Glutamatergic neurons
• Neuronal subtypes
• Retinal neurons
• Transcription factors

• Congenital heart disease
• Creatine kinase
• Embryonic development
• Haemoglobin
• Myoglobin
• Troponin

• Animals
• Cardiovascular System/embryology
• Cardiovascular System/metabolism
• Embryo Loss/pathology
• Erythrocytes/metabolism
• Fetus/metabolism
• Gene Expression Regulation, Developmental
• Hemoglobins/metabolism
• Kruppel-Like Transcription Factors/blood
• Kruppel-Like Transcription Factors/metabolism
• Mice
• Mutation/genetics
• Myocytes, Cardiac/metabolism
• Organ Specificity
• Protein Isoforms/metabolism
• Time Factors
• Troponin I/metabolism
• Tumor Suppressor Proteins/blood
• Tumor Suppressor Proteins/metabolism

• PG/09/065/27893 British Heart Foundation
• RG/15/14/31880 British Heart Foundation

Appel et al. defined the genomic transcription unit encompassing regulatory elements (REs) that mediate the tissue-specific expression of Runx3. Then, using transgenic mice expressing BAC reporters spanning the Runx3 locus, they discovered three REs that cross-talk with promoter-2 (P2) to drive TrkC neuron-specific Runx3 transcription.

The Runx3 transcription factor is essential for development and diversification of the dorsal root ganglia (DRGs) TrkC sensory neurons. In Runx3-deficient mice, developing TrkC neurons fail to extend central and peripheral afferents, leading to cell death and disruption of the stretch reflex circuit, resulting in severe limb ataxia. Despite its central role, the mechanisms underlying the spatiotemporal expression specificities of Runx3 in TrkC neurons were largely unknown. Here we first defined the genomic transcription unit encompassing regulatory elements (REs) that mediate the tissue-specific expression of Runx3. Using transgenic mice expressing BAC reporters spanning the Runx3 locus, we discovered three REs—dubbed R1, R2, and R3—that cross-talk with promoter-2 (P2) to drive TrkC neuron-specific Runx3 transcription. Deletion of single or multiple elements either in the BAC transgenics or by CRISPR/Cas9-mediated endogenous ablation established the REs’ ability to promote and/or repress Runx3 expression in developing sensory neurons. Our analysis reveals that an intricate combinatorial interplay among the three REs governs Runx3 expression in distinct subtypes of TrkC neurons while concomitantly extinguishing its expression in non-TrkC neurons. These findings provide insights into the mechanism regulating cell type-specific expression and subtype diversification of TrkC neurons in developing DRGs.

• BAC transgenic mice
• CRISPR/Cas9 enhancer mutants
• DRG TrkC proprioceptive neurons
• Runx3 transcription factor
• long-range transcription regulatory elements

• Adult stem cells
• DNA methylation
• Differentiation
• Histone modifications
• Retinal cells

• Eya1
• Six1
• cranial placodes
• developmental biology
• sense organs
• stem cells
• xenopus

• development
• dorsal root ganglion
• dorsal spinal cord
• mouse
• transcription factors

The cranial sensory ganglia represent populations of neurons with distinct functions, or sensory modalities. The production of individual ganglia from distinct neurogenic placodes with different developmental pathways provides a powerful model to investigate the acquisition of specific sensory modalities. To date there is a limited range of gene markers available to examine the molecular pathways underlying this process.

Transcriptional profiles were generated for populations of differentiated neurons purified from distinct cranial sensory ganglia using microdissection in embryonic chicken followed by FAC-sorting and RNAseq. Whole transcriptome analysis confirmed the division into somato- versus viscerosensory neurons, with additional evidence for subdivision of the somatic class into general and special somatosensory neurons. Cross-comparison of distinct ganglia transcriptomes identified a total of 134 markers, 113 of which are novel, which can be used to distinguish trigeminal, vestibulo-acoustic and epibranchial neuronal populations. In situ hybridisation analysis provided validation for 20/26 tested markers, and showed related expression in the target region of the hindbrain in many cases.

One hundred thirty-four high-confidence markers have been identified for placode-derived cranial sensory ganglia which can now be used to address the acquisition of specific cranial sensory modalities.

The online version of this article (doi:10.1186/s13064-016-0057-y) contains supplementary material, which is available to authorized users.

SIX1 homeodomain protein is one of the essential key regulators of sensory organ development. Six1-deficient mice lack the olfactory epithelium, vomeronasal organs, cochlea, vestibule and vestibuloacoustic ganglion, and also show poor neural differentiation in the distal part of the cranial ganglia. Simultaneous loss of both Six1 and Six4 leads to additional abnormalities such as small trigeminal ganglion and abnormal dorsal root ganglia (DRG). The aim of this study was to understand the molecular mechanism that controls Six1 expression in sensory organs, particularly in the trigeminal ganglion and DRG. To this end, we focused on the sensory ganglia-specific Six1 enhancer (Six1-8) conserved between chick and mouse. In vivo reporter assays using both animals identified an important core region comprising binding consensus sequences for several transcription factors including nuclear hormone receptors, TCF/LEF, SMAD, POU homeodomain and basic-helix-loop-helix proteins. The results provided information on upstream factors and signals potentially relevant to Six1 regulation in sensory neurons. We also report the establishment of a new transgenic mouse line (mSix1-8-NLSCre) that expresses Cre recombinase under the control of mouse Six1-8. Cre-mediated recombination was detected specifically in ISL1/2-positive sensory neurons of Six1-positive cranial sensory ganglia and DRG. The unique features of the mSix1-8-NLSCre line are the absence of Cre-mediated recombination in SOX10-positive glial cells and central nervous system and ability to induce recombination in a subset of neurons derived from the olfactory placode/epithelium. This mouse model can be potentially used to advance research on sensory development.

• Animals
• Avian Proteins/biosynthesis
• Avian Proteins/genetics
• Chick Embryo
• Chickens/genetics
• Chickens/metabolism
• Enhancer Elements, Genetic
• Ganglia, Spinal/cytology
• Ganglia, Spinal/embryology
• Gene Expression Regulation, Developmental/physiology
• Homeodomain Proteins/biosynthesis
• Homeodomain Proteins/genetics
• Mice
• Mice, Knockout
• Receptors, Cytoplasmic and Nuclear/biosynthesis
• Receptors, Cytoplasmic and Nuclear/genetics
• SOXE Transcription Factors/biosynthesis
• SOXE Transcription Factors/genetics
• Sensory Receptor Cells/metabolism
• Trans-Activators/biosynthesis
• Trans-Activators/genetics
• Trigeminal Ganglion/cytology
• Trigeminal Ganglion/embryology

• in utero MSCs transplantation
• mesenchymal stem cell
• neural tube defects
• prenatal treatment
• sensory neuron regeneration

• Animals
• Basic Helix-Loop-Helix Transcription Factors/genetics
• Basic Helix-Loop-Helix Transcription Factors/physiology
• Female
• Fibroblasts/physiology
• Fibroblasts/ultrastructure
• Humans
• Mice
• Nerve Tissue Proteins/genetics
• Nerve Tissue Proteins/physiology
• Nociceptors/ultrastructure
• Patch-Clamp Techniques
• Peripheral Nervous System/cytology
• Peripheral Nervous System/ultrastructure
• Pregnancy
• Receptor, trkC/genetics
• Sensory Receptor Cells/physiology
• Sensory Receptor Cells/ultrastructure
• Transcription Factor Brn-3A/genetics
• Transcription Factor Brn-3A/physiology

• MH102698 NIMH NIH HHS
• DC012592 NIDCD NIH HHS
• R01 MH102698 NIMH NIH HHS
• DA031566 NIDA NIH HHS
• R01 DC012592 NIDCD NIH HHS
• R21 DA040458 NIDA NIH HHS
• R01 AA021667 NIAAA NIH HHS
• R01 DA031566 NIDA NIH HHS

• Epigenetics
• Fate restriction
• Histone methylation
• Multipotency
• Neural stem cells
• Neuronal differentiation

• migration
• transcription factor
• midbrain
• isoform
• differentiation
• axon

• Animals
• Cell Differentiation/physiology
• Cell Movement/physiology
• Fluorescent Antibody Technique
• Gene Expression Regulation, Developmental
• Homeodomain Proteins/genetics
• Homeodomain Proteins/metabolism
• Hypothalamus/embryology
• Hypothalamus/metabolism
• Immunohistochemistry
• In Situ Hybridization
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Confocal
• Neurogenesis/physiology
• Neurons/cytology
• Neurons/metabolism
• Protein Isoforms/genetics
• Protein Isoforms/metabolism
• Real-Time Polymerase Chain Reaction
• Superior Colliculi/embryology
• Superior Colliculi/metabolism
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Homeobox Protein PITX2

• R01 NS054784 NINDS NIH HHS
• T32 DC000011 NIDCD NIH HHS
• T32-GM007315 NIGMS NIH HHS
• T32-DC00011 NIDCD NIH HHS
• R01 HL093484 NHLBI NIH HHS
• T32 GM007315 NIGMS NIH HHS

• neural crest
• dorsal root ganglion
• melanocyte

• Animals
• Cell Lineage
• Gene Expression Regulation, Developmental
• Gene Regulatory Networks
• Humans
• Melanocytes/cytology
• Melanocytes/physiology
• Multipotent Stem Cells/cytology
• Multipotent Stem Cells/physiology
• Neural Crest/cytology
• Neural Crest/embryology
• Neural Crest/physiology
• Sensory Receptor Cells/cytology
• Sensory Receptor Cells/physiology
• Signal Transduction

• ZIA HG000136-12 Intramural NIH HHS
• Z01 HG000136-09 Intramural NIH HHS
• R01 NS057220 NINDS NIH HHS
• ZIA HG000136-11 Intramural NIH HHS
• R01 NS057220-03 NINDS NIH HHS
• R01 NS057220-02 NINDS NIH HHS
• R01 NS057220-04 NINDS NIH HHS
• Z01 HG000136-10 Intramural NIH HHS
• ZIA HG000070-16 Intramural NIH HHS
• Z01 HG000136 Intramural NIH HHS
• ZIA HG000070-15 Intramural NIH HHS
• ZIA HG000136-13 Intramural NIH HHS
• R01 NS057220-05 NINDS NIH HHS
• R01 NS057220-01A1 NINDS NIH HHS

Copy number variations (CNVs) are a major cause of genetic disruption in the human genome with far more nucleotides being altered by duplications and deletions than by single nucleotide polymorphisms (SNPs). In the multifaceted etiology of autism spectrum disorders (ASDs), CNVs appear to contribute significantly to our understanding of the pathogenesis of this complex disease. A unique resource of 42 extended ASD families was genotyped for over 1 million SNPs to detect CNVs that may contribute to ASD susceptibility. Each family has at least one avuncular or cousin pair with ASD. Families were then evaluated for co-segregation of CNVs in ASD patients. We identified a total of five deletions and seven duplications in eleven families that co-segregated with ASD. Two of the CNVs overlap with regions on 7p21.3 and 15q24.1 that have been previously reported in ASD individuals and two additional CNVs on 3p26.3 and 12q24.32 occur near regions associated with schizophrenia. These findings provide further evidence for the involvement of ICA1 and NXPH1 on 7p21.3 in ASD susceptibility and highlight novel ASD candidates, including CHL1, FGFBP3 and POUF41. These studies highlight the power of using extended families for gene discovery in traits with a complex etiology.

• Adolescent
• Child
• Child Development Disorders, Pervasive/genetics
• Child Development Disorders, Pervasive/pathology
• Child Development Disorders, Pervasive/physiopathology
• Child, Preschool
• DNA Copy Number Variations
• Female
• Genetic Predisposition to Disease/genetics
• Humans
• Male
• Pedigree
• Young Adult

• P01 NS026630 NINDS NIH HHS
• R01 MH080647 NIMH NIH HHS
• R01MH080647 NIMH NIH HHS
• P01NS026630 NINDS NIH HHS

The transcription factor Brn3a, product of the pou4f1 gene, is expressed in most sensory neurons throughout embryogenesis. Prior work has demonstrated a role for Brn3a in the repression of early neurogenic genes; here we describe a second major role for Brn3a in the specification of sensory subtypes in the trigeminal ganglion (TG). Sensory neurons initially co-express multiple Trk-family neurotrophin receptors, but are later marked by the unique expression of TrkA, TrkB or TrkC. Maturation of these sensory subtypes is known to depend on the expression of Runx transcription factors. Newborn Brn3a knockout mice fail to express TrkC, which is associated in the TG with mechanoreceptors, plus a set of functional genes associated with nociceptor subtypes. In embryonic Brn3a^-/- ganglia, the normal expression of Runx3 is never initiated in TrkC⁺ neurons, and Runx1 expression is greatly attenuated in TrkA⁺ nociceptors. These changes are accompanied by expanded expression of TrkB in neurons that abnormally express multiple Trks, followed by the loss of TrkC and TrkA expression. In transgenic embryos expressing a Brn3a-VP16 dominant transactivator, Runx3 mRNA expression is increased, suggesting that it is a direct regulatory target of Brn3a. Chromatin immunoprecipitation confirms that Brn3a binds in vivo to a conserved upstream enhancer element within histone H3-acetylated chromatin in the Runx3 locus. Together these data show that Brn3a acts upstream of the Runx factors, which then repress TrkB expression to allow establishment of the non-overlapping Trk receptor profiles and correct terminally differentiated phenotypes.