CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail

Laura Rusconi, Lisa Salvatoni, Laura Giudici, Ilaria Bertani, Charlotte Kilstrup-Nielsen, Vania Broccoli, Nicoletta Landsberger

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome (RTT), West syndrome, and X-linked infantile spasms, sharing the common feature of mental retardation and early seizures. CDKL5 is a rather uncharacterized kinase, but its involvement in RTT seems to be explained by the fact that it works upstream of MeCP2, the main cause of Rett syndrome. To understand the role of this kinase for nervous system functions and to address if molecular mechanisms are involved in regulating its distribution and activity, we studied the ontogeny of CDKL5 expression in developing mouse brains by immunostaining and Western blotting. The expression profile of CDKL5 was compared with that of MeCP2. The two proteins share a general expression profile in the adult mouse brain, but CDKL5 levels appear to be highly modulated at the regional level. Its expression is strongly induced in early postnatal stages, and in the adult brain CDKL5 is present in mature neurons, but not in astroglia. Interestingly, the presence of CDKL5 in the cell nucleus varies at the regional level of the adult brain and is developmentally regulated. CDKL5 shuttles between the cytoplasm and the nucleus and the C-terminal tail is involved in localizing the protein to the cytoplasm in a mechanism depending on active nuclear export. Accordingly, Rett derivatives containing disease-causing truncations of the C terminus are constitutively nuclear, suggesting that they might act as gain of function mutations in this cellular compartment.

Original languageEnglish
Pages (from-to)30101-30111
Number of pages11
JournalJournal of Biological Chemistry
Volume283
Issue number44
DOIs
Publication statusPublished - Oct 31 2008

Fingerprint

Cyclin-Dependent Kinase 5
Cyclin-Dependent Kinases
Tail
Rett Syndrome
Brain
Cytoplasm
Phosphotransferases
Infantile Spasms
Mutation
Cell Nucleus Active Transport
Neurology
Cell Nucleus
Astrocytes
Intellectual Disability
Nervous System
Neurons
Seizures
Proteins
Genes
Western Blotting

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail. / Rusconi, Laura; Salvatoni, Lisa; Giudici, Laura; Bertani, Ilaria; Kilstrup-Nielsen, Charlotte; Broccoli, Vania; Landsberger, Nicoletta.

In: Journal of Biological Chemistry, Vol. 283, No. 44, 31.10.2008, p. 30101-30111.

Research output: Contribution to journalArticle

Rusconi, Laura ; Salvatoni, Lisa ; Giudici, Laura ; Bertani, Ilaria ; Kilstrup-Nielsen, Charlotte ; Broccoli, Vania ; Landsberger, Nicoletta. / CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 44. pp. 30101-30111.
@article{16e6b58abdf940638cab4bbb7f25a7a5,
title = "CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail",
abstract = "Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome (RTT), West syndrome, and X-linked infantile spasms, sharing the common feature of mental retardation and early seizures. CDKL5 is a rather uncharacterized kinase, but its involvement in RTT seems to be explained by the fact that it works upstream of MeCP2, the main cause of Rett syndrome. To understand the role of this kinase for nervous system functions and to address if molecular mechanisms are involved in regulating its distribution and activity, we studied the ontogeny of CDKL5 expression in developing mouse brains by immunostaining and Western blotting. The expression profile of CDKL5 was compared with that of MeCP2. The two proteins share a general expression profile in the adult mouse brain, but CDKL5 levels appear to be highly modulated at the regional level. Its expression is strongly induced in early postnatal stages, and in the adult brain CDKL5 is present in mature neurons, but not in astroglia. Interestingly, the presence of CDKL5 in the cell nucleus varies at the regional level of the adult brain and is developmentally regulated. CDKL5 shuttles between the cytoplasm and the nucleus and the C-terminal tail is involved in localizing the protein to the cytoplasm in a mechanism depending on active nuclear export. Accordingly, Rett derivatives containing disease-causing truncations of the C terminus are constitutively nuclear, suggesting that they might act as gain of function mutations in this cellular compartment.",
author = "Laura Rusconi and Lisa Salvatoni and Laura Giudici and Ilaria Bertani and Charlotte Kilstrup-Nielsen and Vania Broccoli and Nicoletta Landsberger",
year = "2008",
month = "10",
day = "31",
doi = "10.1074/jbc.M804613200",
language = "English",
volume = "283",
pages = "30101--30111",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "44",

}

TY - JOUR

T1 - CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail

AU - Rusconi, Laura

AU - Salvatoni, Lisa

AU - Giudici, Laura

AU - Bertani, Ilaria

AU - Kilstrup-Nielsen, Charlotte

AU - Broccoli, Vania

AU - Landsberger, Nicoletta

PY - 2008/10/31

Y1 - 2008/10/31

N2 - Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome (RTT), West syndrome, and X-linked infantile spasms, sharing the common feature of mental retardation and early seizures. CDKL5 is a rather uncharacterized kinase, but its involvement in RTT seems to be explained by the fact that it works upstream of MeCP2, the main cause of Rett syndrome. To understand the role of this kinase for nervous system functions and to address if molecular mechanisms are involved in regulating its distribution and activity, we studied the ontogeny of CDKL5 expression in developing mouse brains by immunostaining and Western blotting. The expression profile of CDKL5 was compared with that of MeCP2. The two proteins share a general expression profile in the adult mouse brain, but CDKL5 levels appear to be highly modulated at the regional level. Its expression is strongly induced in early postnatal stages, and in the adult brain CDKL5 is present in mature neurons, but not in astroglia. Interestingly, the presence of CDKL5 in the cell nucleus varies at the regional level of the adult brain and is developmentally regulated. CDKL5 shuttles between the cytoplasm and the nucleus and the C-terminal tail is involved in localizing the protein to the cytoplasm in a mechanism depending on active nuclear export. Accordingly, Rett derivatives containing disease-causing truncations of the C terminus are constitutively nuclear, suggesting that they might act as gain of function mutations in this cellular compartment.

AB - Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome (RTT), West syndrome, and X-linked infantile spasms, sharing the common feature of mental retardation and early seizures. CDKL5 is a rather uncharacterized kinase, but its involvement in RTT seems to be explained by the fact that it works upstream of MeCP2, the main cause of Rett syndrome. To understand the role of this kinase for nervous system functions and to address if molecular mechanisms are involved in regulating its distribution and activity, we studied the ontogeny of CDKL5 expression in developing mouse brains by immunostaining and Western blotting. The expression profile of CDKL5 was compared with that of MeCP2. The two proteins share a general expression profile in the adult mouse brain, but CDKL5 levels appear to be highly modulated at the regional level. Its expression is strongly induced in early postnatal stages, and in the adult brain CDKL5 is present in mature neurons, but not in astroglia. Interestingly, the presence of CDKL5 in the cell nucleus varies at the regional level of the adult brain and is developmentally regulated. CDKL5 shuttles between the cytoplasm and the nucleus and the C-terminal tail is involved in localizing the protein to the cytoplasm in a mechanism depending on active nuclear export. Accordingly, Rett derivatives containing disease-causing truncations of the C terminus are constitutively nuclear, suggesting that they might act as gain of function mutations in this cellular compartment.

UR - http://www.scopus.com/inward/record.url?scp=57649148768&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=57649148768&partnerID=8YFLogxK

U2 - 10.1074/jbc.M804613200

DO - 10.1074/jbc.M804613200

M3 - Article

C2 - 18701457

AN - SCOPUS:57649148768

VL - 283

SP - 30101

EP - 30111

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 44

ER -