Article

Excitatory neurons of the proprioceptive, interoceptive, and arousal hindbrain networks share a developmental requirement for Math1.

Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 12/2009; 106(52):22462-7. DOI: 10.1073/pnas.0911579106
Source: PubMed

ABSTRACT Hindbrain networks important for sensation and arousal contain diverse neuronal populations with distinct projections, yet share specific characteristics such as neurotransmitter expression. The relationship between the function of these neurons, their developmental origin, and the timing of their migration remains unclear. Mice lacking the proneural transcription factor Math1 (Atoh1) lose neurons essential for hearing, balance, and unconscious proprioception. By using a new, inducible Math1(Cre*PR) allele, we found that Math1 is also required for the conscious proprioceptive system, including excitatory projection neurons of the dorsal column nuclei and for vital components of the interoceptive system, such as Barrington's nucleus, that is closely associated with arousal. In addition to specific networks, Math1 lineages shared specific neurotransmitter expression, including glutamate, acetylcholine, somatostatin, corticotropin releasing hormone, and nitric oxide. These findings identify twenty novel Math1 lineages and indicate that the Math1 network functions partly as an interface for conscious (early-born) and unconscious (late-born) proprioceptive inputs to the cortex and cerebellum, respectively. In addition, these data provide previously unsuspected genetic and developmental links between proprioception, interoception, hearing, and arousal.

0 Followers
 · 
87 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The cerebellum is a pre-eminent model for the study of neurogenesis and circuit assembly. Increasing interest in the cerebellum as a participant in higher cognitive processes and as a locus for a range of disorders and diseases make this simple yet elusive structure an important model in a number of fields. In recent years, our understanding of some of the more familiar aspects of cerebellar growth, such as its territorial allocation and the origin of its various cell types, has undergone major recalibration. Furthermore, owing to its stereotyped circuitry across a range of species, insights from a variety of species have contributed to an increasingly rich picture of how this system develops. Here, we review these recent advances and explore three distinct aspects of cerebellar development - allocation of the cerebellar anlage, the significance of transit amplification and the generation of neuronal diversity - each defined by distinct regulatory mechanisms and each with special significance for health and disease.
    Development 11/2014; 141(21):4031-4041. DOI:10.1242/dev.106559 · 6.27 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hindbrain dorsal interneurons (HDIs) are implicated in receiving, processing, integrating, and transmitting sensory inputs from the periphery and spinal cord, including the vestibular, auditory, and proprioceptive systems. During development, multiple molecularly defined HDI types are set in columns along the dorsoventral axis, before migrating along well-defined trajectories to generate various brainstem nuclei. Major brainstem functions rely on the precise assembly of different interneuron groups and higher brain domains into common circuitries. Yet, knowledge regarding interneuron axonal patterns, synaptic targets, and the transcriptional control that govern their connectivity is sparse. The dB1 class of HDIs is formed in a district dorsomedial position along the hindbrain and gives rise to the inferior olive nuclei, dorsal cochlear nuclei, and vestibular nuclei. dB1 interneurons express various transcription factors (TFs): the pancreatic transcription factor 1a (Ptf1a), the homeobox TF-Lbx1 and the Lim-homeodomain (Lim-HD), and TF Lhx1 and Lhx5. To decipher the axonal and synaptic connectivity of dB1 cells, we have used advanced enhancer tools combined with conditional expression systems and the PiggyBac-mediated DNA transposition system in avian embryos. Multiple ipsilateral and contralateral axonal projections were identified ascending toward higher brain centers, where they formed synapses in the Purkinje cerebellar layer as well as at discrete midbrain auditory and vestibular centers. Decoding the mechanisms that instruct dB1 circuit formation revealed a fundamental role for Lim-HD proteins in regulating their axonal patterns, synaptic targets, and neurotransmitter choice. Together, this study provides new insights into the assembly and heterogeneity of HDIs connectivity and its establishment through the central action of Lim-HD governed programs. Copyright © 2015 the authors 0270-6474/15/352596-16$15.00/0.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background information: The vertebrate basic helix-loop-helix transcription factor Atoh1 is essential for maturation and survival of mechanosensory hair cells of the inner ear, neurogenesis, differentiation of the intestine, homeostasis of the colon and is implicated in cancer progression. Given that mutations in Atoh1 are detected in malignant tumors, study of functionally different Atoh1 alleles and homologues might yield useful avenues for investigation. The predicted sequence of chicken Atoh1 (cAtoh1) has large regions of dissimilarity to that of mammalian Atoh1 homologues. We hypothesize that cAtoh1 might have intrinsic functional differences to mammalian Atoh1.Results: In this study we cloned and sequenced the full open reading frame of cAtoh1. In overexpression experiments we show that this sequence is sufficient to generate a cAtoh1 protein capable of inducing hair cell markers when expressed in nonsensory regions of the developing inner ear, and that morpholino-mediated knock-down using a section of the sequence 5’ to the start codon inhibits differentiation of hair cells in the chicken basilar papilla. Furthermore, we compare the behavior of cAtoh1 and human Atoh1 (hAtoh1) in embryonic mouse cochlear explants, showing that cAtoh1 is a potent inducer of hair cell differentiation and that it can overcome Sox2 mediated repression of hair cell differentiation more effectively than human Atoh1.Conclusions: cAtoh1 is both necessary and sufficient for avian mechanosensory hair cell differentiation. The non-conserved regions of the cAtoh1 coding region have functional consequences on its behavior.This article is protected by copyright. All rights reserved
    Biology of the Cell 11/2014; DOI:10.1111/boc.201400078 · 3.87 Impact Factor

Full-text (2 Sources)

Download
16 Downloads
Available from
Jun 10, 2014