1: Glia. 2004 Oct;48(1):14-26. 

Early stages of oligodendrocyte development in the embryonic murine spinal cord
proceed normally in the absence of Hoxa2.

Nicolay DJ, Doucette JR, Nazarali AJ.

Laboratory of Molecular Biology, College of Pharmacy and Nutrition, University
of Saskatchewan, Saskatoon, Saskatchewan.

Recent discoveries have enhanced our knowledge of the transcriptional control of
oligodendrocyte (OG) development. In particular, the transcription factors (TFs)
Olig2, Pax6, and Nkx2.2 have been shown to be important in the specification
and/or maturation of the OG lineage. Although numerous other TFs are expressed
by OGs, little is known regarding their role(s) in oligodendrogenesis. One such
TF is the homeobox gene Hoxa2, which was recently shown to be expressed by O4(+)
pro-oligodendrocytes. The objectives of this study were to examine the
expression of Hoxa2 during the early stages of OG development, as well as to
determine whether Hoxa2 is required for specification and/or early maturation of
OGs. Immunocytochemical analysis of primary mixed glial cultures demonstrated
that Hoxa2 was expressed throughout oligodendrogenesis, diminishing only with
the acquisition of a myelinating phenotype. Serial transverse spinal cord
sections from embryonic days 12.5, 14.25, 16, and 18 Hoxa2(+/+), Hoxa2(+/-), and
Hoxa2(-/-) mice were subjected to single and double immunohistochemical analysis
in order to examine Hoxa2, Olig2, Nkx2.2, and Pax6 expression profiles. Results
obtained from Hoxa2(+/+) and Hoxa2(+/-) mice suggested that Hoxa2 was expressed
by migratory oligodendroglial cells. In addition, comparison of spinal cord
sections obtained from Hoxa2(+/+), Hoxa2(+/-), and Hoxa2(-/-) mice suggested
that specification and early maturation of OGs proceeded normally in the absence
of Hoxa2, since there were no obvious alterations in the expression patterns of
Olig2, Nkx2.2, and/or Pax6. Hence, although Hoxa2 is expressed throughout OG
development, it does not appear to be critical for early stages of
oligodendrogenesis in the murine spinal cord.

PMID: 15326611 [PubMed - indexed for MEDLINE]


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2: Development. 2003 Nov;130(21):5191-201. Epub 2003 Sep 3. 

Hox3 genes coordinate mechanisms of genetic suppression and activation in the
generation of branchial and somatic motoneurons.

Gaufo GO, Thomas KR, Capecchi MR.

Howard Hughes Medical Institute, Department of Human Genetics, University of
Utah, Salt Lake City, UT 84112, USA.

In the developing hindbrain, the functional loss of individual Hox genes has
revealed some of their roles in specifying rhombomere (r) identity. However, it
is unclear how Hox genes act in concert to confer the unique identity to
multiple rhombomeres. Moreover, it remains to be elucidated how these genes
interact with other transcriptional programs to specify distinct neuronal
lineages within each rhombomere. We demonstrate that in r5, the combined
mutation of Hoxa3 and Hoxb3 result in a loss of Pax6- and Olig2-expressing
progenitors that give rise to somatic motoneurons of the abducens nucleus. In
r6, the absence of any combination of the Hox3 paralogous genes results in
ectopic expression of the r4-specific determinant Hoxb1. This ectopic expression
in turn results in the differentiation of r4-like facial branchiomotoneurons
within this rhombomere. These studies reveal that members of the Hox1 and Hox3
paralogous groups participate in a 'Hox code' that is necessary for coordinating
both suppression and activation mechanisms that ensure distinction between the
multiple rhombomeres in the developing hindbrain.

PMID: 12954718 [PubMed - indexed for MEDLINE]


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3: Neuroreport. 2001 Feb 12;12(2):329-33. 

Coordinated expression of Hoxa2, Hoxd1 and Pax6 in the developing diencephalon.

Wolf LV, Yeung JM, Doucette JR, Nazarali AJ.

Laboratory of Molecular Biology, College of Pharmacy and Nutrition, University
of Saskatchewan, Saskatoon, Canada.

Coordinated expression of Hoxa2, Hoxd1 and Pax6 proteins were found to coincide
with the three developmental stages of the diencephalon, as described for the
mouse brain. In the first stage (embryonic day (E) 10-12) Hoxa2, Hoxd1 and Pax6
(an early marker gene of the diencephalon) were expressed as early as E10.5 in
prosomeres (p), p2 and p3. All three proteins continue to exhibit overlapping
domains of expression at E12.5-13 (beginning of the second stage) when the
primitive dense cell layer begins to differentiate into the internal germinal,
external germinal and mantle layers. Towards the end of the second stage (E15),
Pax6 expression was down-regulated whereas Hoxa2 and Hoxd1 continued to exhibit
overlapping domains of expression for both protein and mRNA. Hoxd1 expression
decreased significantly in the third stage of diencephalic development
(E16-postnatal) such that only Hoxa2 expression persisted in the diencephalon of
newborn mice. The temporal and spatial expression of these three proteins imply
that coordinated waves of Hoxa2, Hoxd1 and Pax6 expression may be required to
provide positional information for the specification of the diencephalon.

PMID: 11209945 [PubMed - indexed for MEDLINE]


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4: Development. 2000 Jan;127(2):307-17. 

Regulation of mouse lens fiber cell development and differentiation by the Maf
gene.

Ring BZ, Cordes SP, Overbeek PA, Barsh GS.

Department of Pediatrics, Howard Hughes Medical Institute, Stanford, California
94305-5428, USA.

Maf is a basic domain/leucine zipper domain protein originally identified as a
proto-oncogene whose consensus target site in vitro, the T-MARE, is an extended
version of an AP-1 site normally recognized by Fos and Jun. Maf and the closely
related family members Neural retina leucine zipper (Nrl), L-Maf, and Krml1/MafB
have been implicated in a wide variety of developmental and physiologic roles;
however, mutations in vivo have been described only for Krml1/MafB, in which a
loss-of-function causes abnormalities in hindbrain development due to failure to
activate the Hoxa3 and Hoxb3 genes. We have used gene targeting to replace Maf
coding sequences with those of lacZ, and have carried out a comprehensive
analysis of embryonic expression and the homozygous mutant phenotype in the eye.
Maf is expressed in the lens vesicle after invagination, and becomes highly
upregulated in the equatorial zone, the site at which self-renewing anterior
epithelial cells withdraw from the cell cycle and terminally differentiate into
posterior fiber cells. Posterior lens cells in Maf(lacZ) mutant mice exhibit
failure of elongation at embryonic day 11.5, do not express (&agr;)A- and all of
the (beta)-crystallin genes, and display inappropriately high levels of DNA
synthesis. This phenotype partially overlaps with those reported for gene
targeting of Prox1 and Sox1; however, expression of these genes is grossly
normal, as is expression of Eya1, Eya2, Pax6, and Sox2. Recombinant Maf protein
binds to T-MARE sites in the (alpha)A-, (beta)B2-, and (beta)A4-crystallin
promoters but fails to bind to a point mutation in the (alpha)A-crystallin
promoter that has been shown previously to be required for promoter function.
Our results indicate that Maf directly activates many if not all of the
(beta)-crystallin genes, and suggest a model for coordinating cell cycle
withdrawal with terminal differentiation.

PMID: 10603348 [PubMed - indexed for MEDLINE]


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