Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain

Foxp2 and Foxp1 are recently identified members of the Fox family of winged‐helix/forkhead transcription factor genes. A recent study has found that mutations in human FOXP2 produce a severe language disorder. Since Foxp2 appears to be important in language, we wanted to explore the expression of this gene and a homologous gene, Foxp1, in the developing brain. In the present study, we investigated the time course and localization of Foxp2 and Foxp1 mRNA and protein expression in the developing and adult mouse using in situ hybridization and immunohistochemistry. Foxp2 and Foxp1 are expressed as early as E12.5 and persist into adulthood. Foxp2 and Foxp1 were most highly expressed in the developing and mature basal ganglia. Expression of Foxp2 was also observed in the cerebral cortex (layer 6), cerebellum (Purkinje neurons), and thalamus. Foxp1 expression was observed in the cerebral cortex (layers 3–5), hippocampus (CA1), and thalamus. Very little ventricular zone expression was observed for Foxp2 and Foxp1 and the expression of both of these genes occurred following neuronal migration, suggesting a role for these genes in postmigratory neuronal differentiation. Furthermore, we demonstrated the expression of FOXP2 in human fetal brain by RT‐PCR, in the perisylvian area of the left and right cerebral hemispheres, as well as in the frontal and occipital cortices. Overall, the widespread expression of Foxp2 in the developing brain makes it difficult to draw specific conclusions about which areas of Foxp2 expression are critical to human language function. J. Comp. Neurol. 460:266–279, 2003. © 2003 Wiley‐Liss, Inc.

[1]  P. Gruss,et al.  Expression of Foxb1 Reveals Two Strategies for the Formation of Nuclei in the Developing Ventral Diencephalon , 2000, Developmental Neuroscience.

[2]  T. Curran,et al.  A protein related to extracellular matrix proteins deleted in the mouse mutant reeler , 1995, Nature.

[3]  Weiguo Shu,et al.  Characterization of a New Subfamily of Winged-helix/Forkhead (Fox) Genes That Are Expressed in the Lung and Act as Transcriptional Repressors* , 2001, The Journal of Biological Chemistry.

[4]  A R Damasio,et al.  Aphasia with nonhemorrhagic lesions in the basal ganglia and internal capsule. , 1982, Archives of neurology.

[5]  K. Kaestner,et al.  Expression of the winged helix genes fkh-4 and fkh-5 defines domains in the central nervous system , 1996, Mechanisms of Development.

[6]  A. Pearlman,et al.  Abnormal reorganization of preplate neurons and their associated extracellular matrix: An early manifestation of altered neocortical development in the reeler mutant mouse , 1997, The Journal of comparative neurology.

[7]  S. Xuan,et al.  Winged helix transcription factor BF-1 is essential for the development of the cerebral hemispheres , 1995, Neuron.

[8]  R. Sidman,et al.  Time of origin of corresponding cell classes in the cerebral cortex of normal and reeler mutant mice: An autoradiographic analysis , 1973, The Journal of comparative neurology.

[9]  P. Gruss,et al.  The fork head transcription factor Fkh5/Mf3 is a developmental marker gene for superior colliculus layers and derivatives of the hindbrain somatic afferent zone. , 1999, Brain research. Developmental brain research.

[10]  M. Raichle,et al.  Linguistic processing. , 1997, International review of neurobiology.

[11]  R. Ingham,et al.  A PET study of the neural systems of stuttering , 1996, Nature.

[12]  F. Guillemot,et al.  Mash1 regulates neurogenesis in the ventral telencephalon. , 1999, Development.

[13]  Karl J. Friston,et al.  MRI analysis of an inherited speech and language disorder: structural brain abnormalities. , 2002, Brain : a journal of neurology.

[14]  Karl J. Friston,et al.  Neural basis of an inherited speech and language disorder. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[15]  P. Gruss,et al.  Fkh5-deficient mice show dysgenesis in the caudal midbrain and hypothalamic mammillary body. , 1997, Development.

[16]  B. Hogan,et al.  The winged helix gene, Mf3, is required for normal development of the diencephalon and midbrain, postnatal growth and the milk-ejection reflex. , 1997, Development.

[17]  U. Berger,et al.  Differential distribution of the glutamate transporters GLT‐1 and GLAST in tanycytes of the third ventricle , 2001, The Journal of comparative neurology.

[18]  A. Monaco,et al.  A forkhead-domain gene is mutated in a severe speech and language disorder , 2001, Nature.

[19]  Michael P. Kaschak,et al.  Neuroimaging studies of language production and comprehension. , 2003, Annual review of psychology.

[20]  H. Whitaker,et al.  Acquired capsular/striatal aphasia in childhood. , 1983, Archives of neurology.

[21]  Philip Lieberman,et al.  Speech production, syntax comprehension, and cognitive deficits in Parkinson's disease , 1992, Brain and Language.

[22]  P Gruss,et al.  Winged helix transcription factor Foxb1 is essential for access of mammillothalamic axons to the thalamus. , 2000, Development.

[23]  J. Rubenstein,et al.  Tbr1 Regulates Differentiation of the Preplate and Layer 6 , 2001, Neuron.

[24]  F. Vargha-Khadem,et al.  Behavioural analysis of an inherited speech and language disorder: comparison with acquired aphasia. , 2002, Brain : a journal of neurology.

[25]  E. Lai,et al.  Telencephalon-restricted expression of BF-1, a new member of the HNF-3/fork head gene family, in the developing rat brain , 1992, Neuron.

[26]  J. Rubenstein,et al.  Cortical and thalamic axon pathfinding defects in Tbr1, Gbx2, and Pax6 mutant mice: Evidence that cortical and thalamic axons interact and guide each other , 2002, The Journal of comparative neurology.

[27]  J. Richardson,et al.  Correct Coordination of Neuronal Differentiation Events in Ventral Forebrain Requires the bHLH Factor MASH1 , 1999, Molecular and Cellular Neuroscience.

[28]  S. Anderson,et al.  Mutations of the Homeobox Genes Dlx-1 and Dlx-2 Disrupt the Striatal Subventricular Zone and Differentiation of Late Born Striatal Neurons , 1997, Neuron.

[29]  Laura Ann Petitto,et al.  Left Hemisphere Cerebral Specialization for Babies While Babbling , 2002, Science.

[30]  S Rozen,et al.  Primer3 on the WWW for general users and for biologist programmers. , 2000, Methods in molecular biology.

[31]  M. Lu,et al.  Foxp4: a novel member of the Foxp subfamily of winged-helix genes co-expressed with Foxp1 and Foxp2 in pulmonary and gut tissues , 2002, Mechanisms of Development.

[32]  S. Anderson,et al.  Distinct cortical migrations from the medial and lateral ganglionic eminences. , 2001, Development.

[33]  C Büchel,et al.  Brain regions involved in articulation , 1999, The Lancet.

[34]  D Le Bihan,et al.  Magnetic Resonance Imaging Functional Activation of Left Frontal Cortex During Covert Word Production , 1994, Journal of neuroimaging : official journal of the American Society of Neuroimaging.

[35]  Kevin Murphy,et al.  Speech production: Wernicke, Broca and beyond. , 2002, Brain : a journal of neurology.

[36]  Simon E. Fisher,et al.  Localisation of a gene implicated in a severe speech and language disorder , 1997, Nature Genetics.