Regulation of tyrosine hydroxylase expression

Details Regulation of tyrosine hydroxylase expression Regulation of tyrosine hydroxylase expression

1999-03-26

2001-11-06

Prouty, Rebecca E. (Department: 1652)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

C435S006120, C435S069100, C435S455000, C435S183000, C435S189000, C435S368000, C536S023100

Reexamination Certificate

active

06312949

ABSTRACT:

BACKGROUND
1. Technical Field
The invention relates generally to neural progenitor cells and more specifically to the regulation of tyrosine hydroxylase expression and treatment of catecholamine-related diseases.
2. Background Information
During development, neural stem cells differentiate into the different types of neurons and glia found in the adult central nervous system (CNS) and peripheral nervous system (PNS). In general, these different types of neurons are classified based on the particular types of neurotransmitters they produce. For example, dopaminergic neurons produce dopamine, while noradrenergic neurons produce norepinephrine. The neurotransmitters dopamine and norepinephrine belong to a class of compounds called catecholamines. A catecholamine is an ortho-dihydroxyphenylalkylamine that is derived from the common cellular metabolite tyrosine. For example, the catecholamines dopamine and norepinephrine are synthesized from tyrosine as follows: tyrosine is converted to dihydroxyphenylalamine (DOPA) by the enzyme tyrosine hydroxylase (TH), DOPA to dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC), and dopamine to norepinephrine by the enzyme dopamine &bgr;-hydroxylase (DBH). The rate limiting step for both dopamine and norepinephrine synthesis is the conversion of tyrosine into DOPA by TH. In addition, dopamine can be converted to dihydroxyphenylacetic acid (DOPAC) by the enzymes monoamine oxidase (MAO) and aldehyde dehydrogenase.
The exact mechanisms that regulate neuronal phenotype or even neuronal cell fate determination are not well understood. Developmental studies, however, have identified some genes that appear involved. Briefly, vertebrate nervous systems develop in stereotypic positions along the dorso-ventral (D-V) and anterior-posterior (A-P) axes of the neural tube (Tanabe et al.,
Science
274:1115-1123 (1996)). Transplantation and explant culture studies confirmed that signaling centers instruct cell fates along the A-P and D-V axes. A characteristic common to these centers is the interaction of receptor-ligand pairs to modify cell fate. Sonic hedgehog (Shh) and bone morphogenetic protein (BMP) are two such polypeptides that regulate cell fate along the D-V axis. Fibroblast growth factor-2 (FGF-2), FGF-8, retinoic acid (RA), and Wnt1 influence cell fate along the A-P axis. In each case, signaling induces downstream changes that are reflected in the patterning of transcription factor expression (Crossley et al.,
Nature
380:66-68 (1996); Lumsden and Krumlauf,
Science
274:1109-1114 (1996); Shimamura et al.,
Development
124:2709-2718 (1997); and Vollmer et al,
J. Neurochem.
71:1-19 (1998)).
Using explant cultures, intersections of Shh and FGF-8 signaling created induction sites for dopaminergic neurons in the midbrain and forebrain (Ye et al.,
Cell
93:755-766 (1998)). In addition, Nurr1, an orphan receptor belonging to the nuclear receptor superfamily (Law et al.,
Mol. Endocrinol.
6:2192-2135 (1992) and Zetterstrom et al.,
Mol. Endocrinol.
10:1656-1666 (1996)), and the bicoid-related homeobox factor Ptx3/Pitx3 (Semina et al.,
Human Mol. Genet.
6:2109-2116 (1997); Semina et al.,
Nature Genet.
19:167-170 (1998); and Smidt et al.,
Proc. Natl. Acad. Sci. USA
94:13305-13310 (1997)) appear to be involved in midbrain dopaminergic determination.
Briefly, Nurr1 is expressed at embryonic day (E) 10.5 in the ventral aspect of the mesencephalic flexure and continues to be expressed into adulthood (Zetterstrom et al.,
Mol. Endocrinol.
10:1656-1666(1996) and Zetterstrom et al.,
Mol. Brain Res.
41:111-120(1996)). Ptx3 is expressed in ventral midbrain starting at E11.5, soon after Nurr1 begins to be expressed (Smidt et al.,
Proc. Natl. Acad. Sci. USA
94:13305-13310 (1997) and Saucedo-Cawdenas et al.,
Proc. Natl. Acad. Sci. USA
95:4013-4018 (1998)). Nurr1-null mice lack midbrain dopaminergic neurons and die within 24 h after birth (Zetterstrom et al.,
Science
276:248-250 (1997); Saucedo-Cawdenas et al.,
Proc. Natl. Acad. Sci. USA
95:4013-4018 (1998); and Castillo et al.,
Mol. Cell. Neurosci.
11:36-46 (1998)). In addition, dopamine is absent in the substantia nigra and ventral tegmental area of Nurr1-null mice (Castillo et al.,
Mol. Cell. Neurosci.
11:36-46 (1998)). However, TH immunoreactivity and mRNA expression in hypothalamic, olfactory, and lower brain stem regions were unaffected, and DOPA treatments, whether given to the pregnant dams or to the newborns, failed to rescue the Nurr1-null mice (Castillo et al.,
Mol. Cell. Neurosci.
11:36-46 (1998)).
SUMMARY
The present invention relates to the regulation of tyrosine hydroxylase expression and treatment of catecholamine-related diseases. Specifically, the invention provides cells that contain exogenous nucleic acid having a nucleic acid sequence that encodes Nurr1 (SEQ ID NO:1) as well as methods and materials for inducing tyrosine hydroxylase expression, treating catecholamine-related deficiencies, and identifying tyrosine hydroxylase-related deficiencies.
The present invention is based on the discovery that expression of Nurr1 polypeptide induces tyrosine hydroxylase expression in cells derived from an adult mammal. Specifically, expression of Nurr1 polypeptide induces TH expression in both differentiated and undifferentiated adult rat-derived hippocampal progenitor cells (AHPs). In addition, AHPs overexpressing Nurr1 can produce elevated levels of DOPA and DOPAC, indicating that the TH expression induced by Nurr1 expression results in functional TH enzyme.
The present invention also is based on the discovery that Nurr1 polypeptide induces tyrosine hydroxylase expression by binding directly to the TH promoter. Specifically, Nurr1 polypeptide was found to bind directly to the TH promoter region at positions −873 to −866 (5′-AAAGGTCA-3′;). Since mutations within this Nurr1-binding element of the tyrosine hydroxylase promoter region can result in reduced reporter gene expression and thus tyrosine hydroxylase-related deficiencies, such deficiencies can be identified by assessing the nucleic acid sequence within the TH promoter. Clearly, identifying a tyrosine hydroxylase-related deficiency within a mammal can provide useful information for directing medical practitioners to appropriate treatments.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.


REFERENCES:
patent: WO 94/04675 (1994-03-01), None
Nakagawa et al., Roles of cell autonomous mechanisms for differential expression of region-specific transcription factors in neuroepithelial cells, Development 122: 2449-2464, 1996.*
Scearce et al., RNR-1, a Nuclear Receptor in the NGFI-B/Nur77 Family That Is Rapidly Induced in Regenerating Liver, J. Biol. Chem. 268(12): 8855-8861, Apr. 1993.*
Castillo et al. Dopamine Biosynthesis Is Selectively Abolished in Substantia Nigra/Ventral Tegumental Area but Not in Hypothalmic Neurons in Mice with Targeted Disruption on the Nurr1 Gene, Mol. Cell. Neuroscience 11: 36-46, Mar. 1998.*
Law et al. Identification of a New Brain-Specific Transcription Factor, NURR1, Mol. Endocrinol. 6(12): 2129-2135, 1992.

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