Identification of Positionally Distinct Astrocyte Subtypes whose Identities Are Specified by a Homeodomain Code

Abstract

Astrocytes constitute the most abundant cell type in the central nervous system (CNS) and play diverse functional roles, but the ontogenetic origins of this phenotypic diversity are poorly understood. We have investigated whether positional identity, a fundamental organizing principle governing the generation of neuronal subtype diversity, is also relevant to astrocyte diversification. We identified three positionally distinct subtypes of white-matter astrocytes (WMA) in the spinal cord, which can be distinguished by the combinatorial expression of Reelin and Slit1. These astrocyte subtypes derive from progenitor domains expressing the homeodomain transcription factors Pax6 and Nkx6.1, respectively. Loss- and gain-of-function experiments indicate that the positional identity of these astrocyte subtypes is controlled by Pax6 and Nkx6.1 in a combinatorial manner. Thus, positional identity is an organizing principle underlying astrocyte, as well as neuronal, subtype diversification and is controlled by a homeodomain transcriptional code whose elements are reutilized following the specification of neuronal identity earlier in development.

Regulated temporal-spatial astrocyte precursor cell proliferation involves BRAF signalling in mammalian spinal cord

“…3). These findings are consistent with other domain-regulated developmental mechanisms that have been previously shown (Muroyama et al, 2005;Hochstim et al, 2008). However, further work is needed to distinguish whether the ultimate astrocytes populations in a region might also comprise cells that have migrated from other developmental domains.…”

Affected astrocytes in the spinal cord of the leukodystrophy vanishing white matter

“…Vimentin is expressed in the rodent spinal cord from E11 onwards (Oudega & Marani, 1991; Schnitzer, Franke, & Schachner, 1981). Three distinct subtypes of WM astrocytes can be discriminated in the developing spinal cord: Pax6 and Reelin‐expressing astrocytes in p1 domain (VA1); Pax6‐, Reelin‐, Nkx6.1‐, and Slit1‐expressing astrocytes in ventral p2 domain (VA2); and Nkx6.1‐ and Slit1‐expressing astrocytes in p3 domain (VA3; Hochstim, Deneen, Lukaszewicz, Zhou, & Anderson, 2008). Olig2 is expressed in the ventral spinal cord motor neuron domain (pMn), and gives rise to motor neurons and oligodendrocytes.…”

Regulation of spinal interneuron development by the Olig-related protein Bhlhb5 and Notch signaling

“…Once formed, neural progenitor domains in the spinal cord typically produce multiple classes of neurons as well as glial cells later in development (Muroyama et al, 2005;Del Barrio et al, 2007;Peng et al, 2007;Hochstim et al, 2008;Rousso et al, 2008). This additional level of neuronal diversification has been attributed to two distinct mechanisms.…”