Barhl1 is required for maintenance of a large population of neurons in the zonal layer of the superior colliculus

Li, Shengguo; Xiang, Mengqing

doi:10.1002/dvdy.20858

Cited by 14 publications

(17 citation statements)

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“…Interestingly, deletion of the mouse Barhl1 gene, which encodes a BarH homeodomain protein, leads to progressive degeneration of cochlear hair cells and loss of many neurons from the zonal layer of the superior colliculus due to increased apoptosis in these regions (Li et al 2002;Li and Xiang 2006). These observations suggest that BarH homeodomain proteins may play a conserved role in promoting the survival of sensory neurons.…”

Section: Discussionmentioning

confidence: 93%

Control of sex-specific apoptosis in C. elegans by the BarH homeodomain protein CEH-30 and the transcriptional repressor UNC-37/Groucho

Peden¹,

Kimberly²,

Gengyo-Ando³

et al. 2007

Genes Dev.

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Apoptosis is essential for proper development and tissue homeostasis in metazoans. It plays a critical role in generating sexual dimorphism by eliminating structures that are not needed in a specific sex. The molecular mechanisms that regulate sexually dimorphic apoptosis are poorly understood. Here we report the identification of the ceh-30 gene as a key regulator of sex-specific apoptosis in Caenorhabditis elegans. Loss-of-function mutations in ceh-30 cause the ectopic death of male-specific CEM neurons. ceh-30 encodes a BarH homeodomain protein that acts downstream from the terminal sex determination gene tra-1, but upstream of, or in parallel to, the cell-death-initiating gene egl-1 to protect CEM neurons from undergoing apoptosis in males. The second intron of the ceh-30 gene contains two adjacent cis-elements that are binding sites for TRA-1A and a POU-type homeodomain protein UNC-86 and acts as a sensor to regulate proper specification of the CEM cell fate. Surprisingly, the N terminus of CEH-30 but not its homeodomain is critical for CEH-30's cell death inhibitory activity in CEMs and contains a conserved eh1/FIL domain that is important for the recruitment of the general transcriptional repressor UNC-37/Groucho. Our study suggests that ceh-30 defines a critical checkpoint that integrates the sex determination signal TRA-1 and the cell fate determination and survival signal UNC-86 to control the sex-specific activation of the cell death program in CEMs through the general transcription repressor UNC-37.[Keywords: C. elegans; apoptosis; sex-specific; unc-37/Groucho; ceh-30; transcriptional regulation] Supplemental material is available at http://www.genesdev.org.

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Section: Discussionmentioning

confidence: 93%

Control of sex-specific apoptosis in C. elegans by the BarH homeodomain protein CEH-30 and the transcriptional repressor UNC-37/Groucho

Peden¹,

Kimberly²,

Gengyo-Ando³

et al. 2007

Genes Dev.

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“…In the developing CNS, Barhl1 and Barhl2 are expressed in the superior and inferior colliculi of the midbrain, the cerebellar granule cells and precerebellar neurons of the hindbrain, and the dorsal interneurons of the spinal cord (4,19,20,26,31,32). Analyses of Barhl1-deficient mice have revealed a crucial role for Barhl1 in the migration and survival of cerebellar and precerebellar neurons and the long-term maintenance of superior collicular neurons as well (19,20). In the spinal cord, Barhl1 inactivation results in no appreciable change, yet gain-of-function studies have implied a role for Barhl2 in the differentiation of dorsal commissural sensory neurons (19,31,32), suggesting a likely functional redundancy between Barhl1 and Barhl2 during spinal neurogenesis.…”

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confidence: 99%

“…The targeted disruption of Barhl1 leads to hearing loss as a result of the age-related progressive degeneration of inner and outer hair cells in the organ of Corti (18), demonstrating a critical requirement for Barhl1 in the longterm maintenance of these sensory cells. In the developing CNS, Barhl1 and Barhl2 are expressed in the superior and inferior colliculi of the midbrain, the cerebellar granule cells and precerebellar neurons of the hindbrain, and the dorsal interneurons of the spinal cord (4,19,20,26,31,32). Analyses of Barhl1-deficient mice have revealed a crucial role for Barhl1 in the migration and survival of cerebellar and precerebellar neurons and the long-term maintenance of superior collicular neurons as well (19,20).…”

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confidence: 99%

Barhl1 Regulatory Sequences Required for Cell-Specific Gene Expression and Autoregulation in the Inner Ear and Central Nervous System

Chellappa¹,

Li²,

Pauley

et al. 2008

Molecular and Cellular Biology

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The development of the nervous system requires the concerted actions of multiple transcription factors, yet the molecular events leading to their expression remain poorly understood. Barhl1, a mammalian homeodomain transcription factor of the BarH class, is expressed by developing inner ear hair cells, cerebellar granule cells, precerebellar neurons, and collicular neurons. Targeted gene inactivation has demonstrated a crucial role for Barhl1 in the survival and/or migration of these sensory cells and neurons. Here we report the regulatory sequences of Barhl1 necessary for directing its proper spatiotemporal expression pattern in the inner ear and central nervous system (CNS). Using a transgenic approach, we have found that high-level and cell-specific expression of Barhl1 within the inner ear and CNS depends on both its 5 promoter and 3 enhancer sequences. Further transcriptional, binding, and mutational analyses of the 5 promoter have identified two homeoprotein binding motifs that can be occupied and activated by Barhl1. Moreover, proper Barhl1 expression in inner ear hair cells and cerebellar and precerebellar neurons requires the presence of Atoh1. Together, these data delineate useful Barhl1 regulatory sequences that direct strong and specific gene expression to inner ear hair cells and CNS sensory neurons, establish a role for autoregulation in the maintenance of Barhl1 expression, and identify Atoh1 as a key upstream regulator.The mammalian Barhl1 and Barhl2 proteins belong to the BarH class of homeodomain transcription factors that are evolutionarily conserved in both invertebrate and vertebrate species ranging from Drosophila flies to humans. The factors of this class are usually expressed in the developing and adult nervous systems and are required for proper neural development and survival (4, 7, 12, 13, 15, 18-20, 24, 26-32, 34). In Drosophila, BarH1 and BarH2 are coexpressed in cells of the central nervous system (CNS) and the peripheral nervous system and are redundantly required for determining the subtypes of external sensory organs and photoreceptor and primary pigment cells during eye development (12,13,15). The vertebrate Barhl1 and Barhl2 genes similarly display overlapping yet distinct patterns of expression in the CNS and sensory organs, thereby also playing redundant as well as distinct roles during neurogenesis (4, 7, 18-20, 24, 26-29, 31, 32, 34). For instance, Xenopus Barhl2 is expressed in the developing neural plate and retina during Xenopus embryogenesis and plays a key role in patterning the neural plate and specifying retinal ganglion cells (27,29).The functions of mammalian Barhl genes during murine neurogenesis have been extensively investigated previously. In the developing mouse inner ear, Barhl1 but not Barhl2 is specifically expressed in all hair cells of the cochlear and vestibular systems (4, 18). The targeted disruption of Barhl1 leads to hearing loss as a result of the age-related progressive degeneration of inner and outer hair cells in the organ of Corti (18), demonstr...

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“…Specifically, they found that the CES-1-like zinc-finger transcription factor, SLUG, controls PUMA transcription and that the transcription of SLUG in turn can be controlled by the oncoprotein, E2A-HLF (hepatic leukemia factor), which is composed of the DNA binding domain of the CES-2-like bZIP transcription factor HLF and the transactivation domain of the bHLH transcription factor E2A. Furthermore, mammalian or vertebrate homologs of C. elegans TRA-1 (GLI-like transcription factors) and CEH-30 (Barhl1, Barhl2) have been implicated in apoptosis regulation (Li et al, 2002Ruiz i Altaba et al, 2002;Offner et al, 2005;Li and Xiang, 2006). Although the relevant targets of these transcription factors in this context remain to be identified, one prediction is that they will include BH3-only genes.…”

Section: Discussionmentioning

confidence: 99%

egl-1: a key activator of apoptotic cell death in C. elegans

Nehme

Conradt

2008

Oncogene

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Since the discovery of mammalian BIK and BAD in 1995, BH3-only proteins have emerged as key activators of apoptotic cell death in animals as diverse as the nematode, Caenorhabditis elegans, and humans. BH3-only proteins have also emerged as integrators of cell-death signals that determine the life-versus-death decision and that transduce this decision to the central apoptotic machinery through their physical interaction with 'core' BCL-2 family members, such as BCL-2 or BCL-XL. Currently, eight BH3-only proteins have been identified and characterized in mammals, and there is evidence of functional overlap between them. In contrast, only two BH3-only proteins have so far been identified and characterized in C. elegans, EGL-1 and CED-13, and there seems to be only limited functional overlap between them. Combined with the powerful genetic tools available for the analysis of apoptosis in C. elegans, and the ability to study apoptosis at single-cell resolution in this organism, the absence of extensive functional redundancy makes C. elegans an ideal model for studies on BH3-only proteins. In this study, we will review our current understanding of the role and regulation of EGL-1. We will also briefly summarize studies on CED-13, which was identified more recently.Oncogene ( Keywords: BCL-2 family; BH3-only proteins; apoptosis; C. elegans; EGL-1; CED-13The egl-1 storyThe egl-1 gene was originally defined by dominant, gain of function (gf) mutations (Trent et al., 1983;Ellis and Horvitz, 1986). These gf mutations cause the hermaphrodite-specific neurons (referred to as 'HSNs'), which are required for egg laying in Caenorhabditis elegans hermaphrodites, to inappropriately die. egl-1 gf mutations were identified in screens for egg-laying defective or 'Egl' animals, and were carried out in Bob Horvitz's laboratory in the early 1980s (hence the name 'egl-1'). These 'Egl screens' resulted in the identification of a total of seven egl-1 gf mutations. Three of these mutations (n487, n1084 and n1796) cause an Egl phenotype in a semi-dominant manner, and the remaining four mutations (n986, n987, n2164 and n2248) cause an Egl phenotype in a fully dominant manner. The inappropriate death of the HSNs in egl-1 gf mutants can be suppressed by mutations that cause a general block in apoptotic cell death, such as a gf mutation in ced-9, which encodes an anti-apoptotic BCL-2-like protein, or loss-of-function (lf) mutations in either ced-4 or ced-3, which encode an APAF-1-like adapter or a caspase, respectively (Ellis and Horvitz, 1986;Hengartner et al., 1992;Yuan and Horvitz, 1992;Yuan et al., 1993;Hengartner and Horvitz, 1994b). These findings showed that the HSNs in egl-1 gf animals inappropriately die by apoptosis. They also suggested that the egl-1 gene may act upstream of the anti-apoptotic gene, ced-9, and of the pro-apoptotic genes, ced-4 and ced-3; however, the normal function of egl-1 remained unclear because of the lack of egl-1 lf mutations. The lack of egl-1 lf mutations not only made it difficult to determine the normal f...

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Barhl1 is required for maintenance of a large population of neurons in the zonal layer of the superior colliculus

Cited by 14 publications

References 30 publications

Control of sex-specific apoptosis in C. elegans by the BarH homeodomain protein CEH-30 and the transcriptional repressor UNC-37/Groucho

Control of sex-specific apoptosis in C. elegans by the BarH homeodomain protein CEH-30 and the transcriptional repressor UNC-37/Groucho

Barhl1 Regulatory Sequences Required for Cell-Specific Gene Expression and Autoregulation in the Inner Ear and Central Nervous System

egl-1: a key activator of apoptotic cell death in C. elegans

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