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The Batten disease Palmitoyl Protein Thioesterase 1 gene regulates neural specification and axon connectivity during Drosophila embryonic development.

Chu-LaGraff Q, Blanchette C, O'Hern P, Denefrio C - PLoS ONE (2010)

Bottom Line: Ppt1 embryos display numerous neural defects ranging from abnormal cell fate specification in a number of identified precursor lineages in the CNS, missing and disorganized neurons, faulty motoneuronal axon trajectory, and discontinuous, misaligned, and incorrect midline crossings of the longitudinal axon bundles of the ventral nerve cord.Defects in the PNS include a decreased number of sensory neurons, disorganized chordotonal neural clusters, and abnormally shaped neurons with aberrant dendritic projections.These results indicate that Ppt1 is essential for proper neuronal cell fates and organization; and to establish the local environment for proper axon guidance and fasciculation.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Union College, Schenectady, New York, United States of America. chulagrq@union.edu

ABSTRACT
Palmitoyl Protein Thioesterase 1 (PPT1) is an essential lysosomal protein in the mammalian nervous system whereby defects result in a fatal pediatric disease called Infantile Neuronal Ceroids Lipofuscinosis (INCL). Flies bearing mutations in the Drosophila ortholog Ppt1 exhibit phenotypes similar to the human disease: accumulation of autofluorescence deposits and shortened adult lifespan. Since INCL patients die as young children, early developmental neural defects due to the loss of PPT1 are postulated but have yet to be elucidated. Here we show that Drosophila Ppt1 is required during embryonic neural development. Ppt1 embryos display numerous neural defects ranging from abnormal cell fate specification in a number of identified precursor lineages in the CNS, missing and disorganized neurons, faulty motoneuronal axon trajectory, and discontinuous, misaligned, and incorrect midline crossings of the longitudinal axon bundles of the ventral nerve cord. Defects in the PNS include a decreased number of sensory neurons, disorganized chordotonal neural clusters, and abnormally shaped neurons with aberrant dendritic projections. These results indicate that Ppt1 is essential for proper neuronal cell fates and organization; and to establish the local environment for proper axon guidance and fasciculation. Ppt1 function is well conserved from humans to flies; thus the INCL pathologies may be due, in part, to the accumulation of various embryonic neural defects similar to that of Drosophila. These findings may be relevant for understanding the developmental origin of neural deficiencies in INCL.

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Related in: MedlinePlus

Mutant Ppt1 and Ppt1 RNAi knock-down in neurons result in defective axon tracts in the developing CNS.In all panels, S17 embryos were stained with 1D4 antibody. (A) FASII is expressed in three longitudinal connectives at this stage. (B) Ppt1A179T embryos exhibit discontinuous and frayed longitudinal connectives. (C, D) Ppt1 RNAi expression under the control of elav gal4 driver results in a range of axon guidance phenotype including wavy bundles with some faulty axon crossing over the midline (arrow in C); and disorganized and/or broken connectives, and fused commissures (arrows in D). Anterior, up.
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pone-0014402-g005: Mutant Ppt1 and Ppt1 RNAi knock-down in neurons result in defective axon tracts in the developing CNS.In all panels, S17 embryos were stained with 1D4 antibody. (A) FASII is expressed in three longitudinal connectives at this stage. (B) Ppt1A179T embryos exhibit discontinuous and frayed longitudinal connectives. (C, D) Ppt1 RNAi expression under the control of elav gal4 driver results in a range of axon guidance phenotype including wavy bundles with some faulty axon crossing over the midline (arrow in C); and disorganized and/or broken connectives, and fused commissures (arrows in D). Anterior, up.

Mentions: To evaluate the morphology of a more discrete subset of axonal longitudinal connectives, Df(1)446-20, Ppt1A179T, and Ppt1S77F, and trans-heterozygous Ppt1 mutant embryos were stained with mAb1D4. At stage 17, mAb1D4 recognizes the neural adhesion protein Fasciclin II, which is expressed in three discrete axon longitudinal bundles on either side of the midline (Figure 5A; [23]). 50–58% of Ppt1 mutant embryos display abnormal FasII-positive longitudinal connectives ranging from mild to severe (Table 3). Mild defects include loose and defasciculated connectives, wavy in appearance. More severe FasII defects include ectopic midline crossing of the longitudinal connectives, discontinuous connectives in all three FasII bundles, and frayed connectives due to defasciculation (Figure 5B).


The Batten disease Palmitoyl Protein Thioesterase 1 gene regulates neural specification and axon connectivity during Drosophila embryonic development.

Chu-LaGraff Q, Blanchette C, O'Hern P, Denefrio C - PLoS ONE (2010)

Mutant Ppt1 and Ppt1 RNAi knock-down in neurons result in defective axon tracts in the developing CNS.In all panels, S17 embryos were stained with 1D4 antibody. (A) FASII is expressed in three longitudinal connectives at this stage. (B) Ppt1A179T embryos exhibit discontinuous and frayed longitudinal connectives. (C, D) Ppt1 RNAi expression under the control of elav gal4 driver results in a range of axon guidance phenotype including wavy bundles with some faulty axon crossing over the midline (arrow in C); and disorganized and/or broken connectives, and fused commissures (arrows in D). Anterior, up.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3008717&req=5

pone-0014402-g005: Mutant Ppt1 and Ppt1 RNAi knock-down in neurons result in defective axon tracts in the developing CNS.In all panels, S17 embryos were stained with 1D4 antibody. (A) FASII is expressed in three longitudinal connectives at this stage. (B) Ppt1A179T embryos exhibit discontinuous and frayed longitudinal connectives. (C, D) Ppt1 RNAi expression under the control of elav gal4 driver results in a range of axon guidance phenotype including wavy bundles with some faulty axon crossing over the midline (arrow in C); and disorganized and/or broken connectives, and fused commissures (arrows in D). Anterior, up.
Mentions: To evaluate the morphology of a more discrete subset of axonal longitudinal connectives, Df(1)446-20, Ppt1A179T, and Ppt1S77F, and trans-heterozygous Ppt1 mutant embryos were stained with mAb1D4. At stage 17, mAb1D4 recognizes the neural adhesion protein Fasciclin II, which is expressed in three discrete axon longitudinal bundles on either side of the midline (Figure 5A; [23]). 50–58% of Ppt1 mutant embryos display abnormal FasII-positive longitudinal connectives ranging from mild to severe (Table 3). Mild defects include loose and defasciculated connectives, wavy in appearance. More severe FasII defects include ectopic midline crossing of the longitudinal connectives, discontinuous connectives in all three FasII bundles, and frayed connectives due to defasciculation (Figure 5B).

Bottom Line: Ppt1 embryos display numerous neural defects ranging from abnormal cell fate specification in a number of identified precursor lineages in the CNS, missing and disorganized neurons, faulty motoneuronal axon trajectory, and discontinuous, misaligned, and incorrect midline crossings of the longitudinal axon bundles of the ventral nerve cord.Defects in the PNS include a decreased number of sensory neurons, disorganized chordotonal neural clusters, and abnormally shaped neurons with aberrant dendritic projections.These results indicate that Ppt1 is essential for proper neuronal cell fates and organization; and to establish the local environment for proper axon guidance and fasciculation.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Union College, Schenectady, New York, United States of America. chulagrq@union.edu

ABSTRACT
Palmitoyl Protein Thioesterase 1 (PPT1) is an essential lysosomal protein in the mammalian nervous system whereby defects result in a fatal pediatric disease called Infantile Neuronal Ceroids Lipofuscinosis (INCL). Flies bearing mutations in the Drosophila ortholog Ppt1 exhibit phenotypes similar to the human disease: accumulation of autofluorescence deposits and shortened adult lifespan. Since INCL patients die as young children, early developmental neural defects due to the loss of PPT1 are postulated but have yet to be elucidated. Here we show that Drosophila Ppt1 is required during embryonic neural development. Ppt1 embryos display numerous neural defects ranging from abnormal cell fate specification in a number of identified precursor lineages in the CNS, missing and disorganized neurons, faulty motoneuronal axon trajectory, and discontinuous, misaligned, and incorrect midline crossings of the longitudinal axon bundles of the ventral nerve cord. Defects in the PNS include a decreased number of sensory neurons, disorganized chordotonal neural clusters, and abnormally shaped neurons with aberrant dendritic projections. These results indicate that Ppt1 is essential for proper neuronal cell fates and organization; and to establish the local environment for proper axon guidance and fasciculation. Ppt1 function is well conserved from humans to flies; thus the INCL pathologies may be due, in part, to the accumulation of various embryonic neural defects similar to that of Drosophila. These findings may be relevant for understanding the developmental origin of neural deficiencies in INCL.

Show MeSH
Related in: MedlinePlus