Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
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Goals
Understand the biology of miR in general
and in context of neurobiology
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Friday, June 8, 12
!
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ATCG TAGC
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ATCG TAGC
!
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UAGC
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Friday, June 8, 12
Naked DNA
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Naked DNA
Promoter
Exons
3' UTR
Genomic DNA
Enhancers
Introns
UAGC
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Genomic DNA
TF's
Pol II
AGAACANNNTGTTCT
Glucocorticoid Response Element (GRE) CRE, ERE, HSE, SRE, HRE, ISRE, etc.
NUCLEUS
UAGC
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Export
NUCLEUS CYTOPLASM
UAGC
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CYTOPLASM
Translation
3`UTR AAAA
t-RNA
Coding
5`Cap
-UUU-
Mature mRNA
2nd base U UUC UUA UUG CUU CUC CUA CUG AUU AUC AUA AUG GUU GUC GUA GUG (Met/M) Methionine (Ile/I) Isoleucine (Leu/L) Leucine (Phe/F) Phenylalanine UCU UCC UCA UCG CCU CCC CCA CCG ACU ACC ACA ACG GCU (Val/V) Valine GCC GCA GCG (Ala/A) Alanine (Pro/P) Proline (Ser/S) Serine C UAU UAC UAA UAG CAU CAC CAA CAG AAU AAC (Thr/T) Threonine!!!!!!!! AAA AAG GAU GAC GAA GAG (His/H) Histidine (Gln/Q) Glutamine (Asn/N) Asparagine (Lys/K) Lysine (Asp/D) Aspartic acid (Glu/E) Glutamic acid A (Tyr/Y) Tyrosine Stop UGU UGC UGA UGG CGU CGC CGA CGG AGU AGC AGA AGG GGU GGC GGA GGG (Gly/G) Glycine (Ser/S) Serine (Arg/R) Arginine (Arg/R) Arginine G (Cys/C) Cysteine Stop (Trp/W) Tryptophan!!!!
3rd base U C A G U C A G U C A G U C A G
UAGC
Friday, June 8, 12
CYTOPLASM
Translation
3`UTR AAAA
t-RNA
Coding
5`Cap
-UUU-
Mature mRNA
STOP
1st base UUU 2nd base U UUC UUA UUG CUU C CUC CUA CUG AUU A AUC AUA AUG GUU G GUC GUA GUG (Val/V) Valine (Met/M) Methionine (Ile/I) Isoleucine (Leu/L) Leucine (Phe/F) Phenylalanine UCU UCC UCA UCG CCU CCC CCA CCG ACU ACC ACA ACG GCU GCC GCA GCG (Ala/A) Alanine (Pro/P) Proline (Ser/S) Serine C UAU UAC UAA UAG CAU CAC CAA CAG AAU AAC (Thr/T) Threonine!!!!!!!! AAA AAG GAU GAC GAA GAG (His/H) Histidine (Gln/Q) Glutamine (Asn/N) Asparagine (Lys/K) Lysine (Asp/D) Aspartic acid (Glu/E) Glutamic acid A (Tyr/Y) Tyrosine Stop UGU UGC UGA UGG CGU CGC CGA CGG AGU AGC AGA AGG GGU GGC GGA GGG (Gly/G) Glycine (Ser/S) Serine (Arg/R) Arginine (Arg/R) Arginine G (Cys/C) Cysteine Stop (Trp/W) Tryptophan!!!! 3rd base U C A G U C A G U C A G U C A G
UAGC
miR
Friday, June 8, 12
CYTOPLASM
Translation
3`UTR AAAA
t-RNA
Coding
5`Cap
-UUU-
Mature mRNA
STOP
1st base UUU 2nd base U UUC UUA UUG CUU C CUC CUA CUG AUU A AUC AUA AUG GUU G GUC GUA GUG (Val/V) Valine (Met/M) Methionine (Ile/I) Isoleucine (Leu/L) Leucine (Phe/F) Phenylalanine UCU UCC UCA UCG CCU CCC CCA CCG ACU ACC ACA ACG GCU GCC GCA GCG (Ala/A) Alanine (Pro/P) Proline (Ser/S) Serine C UAU UAC UAA UAG CAU CAC CAA CAG AAU AAC (Thr/T) Threonine!!!!!!!! AAA AAG GAU GAC GAA GAG (His/H) Histidine (Gln/Q) Glutamine (Asn/N) Asparagine (Lys/K) Lysine (Asp/D) Aspartic acid (Glu/E) Glutamic acid A (Tyr/Y) Tyrosine Stop UGU UGC UGA UGG CGU CGC CGA CGG AGU AGC AGA AGG GGU GGC GGA GGG (Gly/G) Glycine (Ser/S) Serine (Arg/R) Arginine (Arg/R) Arginine G (Cys/C) Cysteine Stop (Trp/W) Tryptophan!!!! 3rd base U C A G U C A G U C A G U C A G
UAGC
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STOP
UAGC
miR
STOP STOP
UAGC
miR
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STOP
UAGC UAGC
UAGC
miR
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!
miR
UAGC UAGC
UAGC
3'
5' ! !
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STOP
UAGC UAGC
UAGC
miR
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Summary
MicroRNAs Regulate Function at the Protein
Translation Step
STOP
UAGC UAGC
UAGC
miR
UAGC
miR
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pri-miRNA Processing
mRNA
5`Cap
Coding
3`UTR
AAAA
mRNA introns
pre-miRNA (~70 nt) Dicer mature miRNA (~22 nt) Gene Regulation
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Chromosomal Locations
Experimental Data from Major Depression
and HIV - Frontal Cortex
Distribution of chromosomal distances between dysreg miRs in HIV & MDD Distribution if random
Tatro & Scott. PLOS One. (2010)
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MDD
! ! !
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MicroRNA Clustering
About 42% of human miRs are Clustered on Genome The polycistronic organization of miRNA genes may have implications for evolution & selection
Altuvia. Nucleic Acids Res. 2005; 33(8): 26972706.
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and physiological maturation with the development of functional neuronal characteristics and a second selection by synaptic integration into pre-existing hippocampal circuits (Sierra et al., 2010; Encinas and Sierra, 2011). Moreover, AHN generates a whole range of neurogenic cell types that are differentially regulated and may play specic roles in the overall process (Figure 1A). During this slow maturation process, many of the newborn neurons are selected and more than 50% of the newborn GCs die within the rst few weeks after birth (Cameron et al., 1993; Biebl et al., 2000; Kempermann et al., 2003; Hattiangady and Shetty, 2008). The rapid decline during early stages results from active
Although the exact role of newborn neurons in the DG is still under debate, recent data support a functional role for adult-born neurons in learning and memory processes as reviewed in detail elsewhere (Aasebo et al., 2011; Aimone et al., 2011; Koehl and Abrous, 2011; Sahay et al., 2011). We here focus briey on DGdependent memory functions that may decrease with aging. The emerging consensus is that adult-born neurons in the DG play a crucial role in pattern separation, a memory mechanism that permits the differential representation of similar stimuli encoded by hippocampal circuits (Aimone et al., 2009; Sahay et al., 2011; Small et al., 2011). In humans, pattern separation can be assessed by a
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FIGURE 1 | MicroRNas are key regulators in all phases of the adult neurogenesis cascade. Schematic illustration, adapted from (Lucassen et al., 2010), summarizing (A) miRs and targets involved in the regulation of different phases of adult neurogenesis and (B) miRs and targets hypothesized to be involved in the regulation of synaptogenesis during functional integration of
miR is less well-characterized in the integration phase as opposed to expansion and differentiation phases. (B) Regulation of synaptogenesis by miR-132 and miR-137 has been studied in AHN and in other contexts as well. From these observations, described in the text, we hypothesize that the regulatory network(s) depicted in (B) could be engaged in ne-tuning
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Differential evolutionary conservation of genomic regions implies miR-mediated processes, though benecial in development, might be detrimental in aging.
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STOP
miR
UAGC
MiR-132 Suppresses p250GAP, inhibitor of Rho GTPases; facilitates NMDA Receptor Signaling & Dendrite Growth
Summary
MicroRNAs Change Expression over Development MicroRNAs involved in Cellular Process in Brain and
Immunity.
STOP
STOP
UAGC
UAGC UAGC
UAGC
miR
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Resources
MirBase! ! ! ! ! ! ! ! Targetscan! ! ! ! ! ! ! Pictar! ! ! ! ! ! ! ! ! UCSC Genome Browser!!
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