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The formation of connections within the mammalian neocortex is highly regulated by both extracellular guidance mechanisms and intrinsic gene expression programs. There are generally two types of cortical projection neurons: those that project locally and interhemispherically, and those that project to sub-cerebral structures such as the thalamus, hindbrain, and spinal cord. The regulation of cortical projection morphologies is not yet fully understood at the molecular level. Here we report a role for Mllt11 (Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene From Chromosome 1q) in the migration and neurite outgrowth of callosal projection neurons during brain formation. We show that Mllt11 expression is exclusive to developing neurons and is enriched in the developing cortical plate, particularly during the formation of the upper or superficial cortical layers. In cultured primary cortical neurons, Mllt11 is detected in varicosities and growth cones as well as the soma. Using conditional loss-of-function and gain-of-function analysis we show that Mllt11 is a required for neuritogenesis and proper migration of upper layer cortical projection neurons. Loss of Mllt11 in the superficial cortex leads to a severe reduction in fibres crossing the corpus callosum, a progressive loss in the maintenance of upper layer projection neuron gene expression, and dysplasia of dendritic arborisation patterns. Proteomic analysis revealed that Mllt11 associates with cytoskeletal components including stabilized microtubules consistent with a role in neuronal migration and neuritogenesis. Taken together, our findings support a role for Mllt11 in promoting the formation of mature projection neuron morphologies and connectivity in the cerebral cortex.

The neurotrophic factor hypothesis, which is largely based on the neurotrophin family of growth factors (for review, see Levi-Montalcini 1987; Thoenen and Barde 1989; Snider 1994), postulates that trophic factors produced and released by target neurons regulate the survival, differentiation, and morphological growth of their innervating neurons (for review, see Oppenheim 1991; Majdan and Miller 1999). However, recent studies suggest that at least one member of the neurotrophin family, brain-derived neurotrophic factor (BDNF) (Barde et al. 1982; Leibrock et al. 1989), acts as an anterograde trophic factor that is derived from afferent neurons (von Bartheld et al. 1996; Altar et al. 1997; Conner et al. 1997; Fawcett et al. 1998). In particular, BDNF has been localized to both axons and terminals of peripheral (Zhou and Rush 1996; Michael et al. 1997) and central neurons (Conner et al. 1997; Fawcett et al. 1997, 1998), and the TrkB/BDNF receptor (Klein et al. 1991; Soppet et al. 1991) has been localized to neuronal dendrites in both the hippocampus and cortex (Fryer et al. 1996; Yan et al. 1997a), where at least a subpopulation of these receptors is present in postsynaptic densities (Wu et al. 1996; Lin et al. 1998). Moreover, this anterogradely trafficked BDNF has the potential to affect the survival and differentiation of target CNS neurons, at least during development (Fawcett et al. 1998). A number of recent studies also indicate that BDNF is localized to vesicles in presynaptic terminals in vivo (Fawcett et al. 1997; Michael et al. 1997), that it may be released in an activity-dependent fashion (Goodman et al. 1996; Mowla et al. 1999), and that following intense neural activity such as during kindling, Trk receptors are autophosphorylated (Binder et al. 1999), raising the interesting possibility that BDNF secretion in the mature nervous system could be regulated in a manner similar to neuropeptides (Mowla et al. 1999). The consequences of activity-dependent release of BDNF in the mature nervous system might be several. First, BDNF could play a more traditional role in regulating the morphology and, potentially, the survival of mature target neurons, a role analogous to that proposed for anterogradely transported BDNF during development (Fawcett et al. 1998). Second, BDNF could play a novel role for a trophic factor, modulating neuronal excitability either directly and/or by modification of the phosphorylation state of postsynaptic neurotransmitter receptors (Jarvis et al. 1997; Suen et al. 1997; Lin et al. 1998). Finally, postsynaptic signaling events resulting from BDNF-mediated TrkB receptor activation could synergize with signaling events caused by neurotransmitter receptor activation and/or calcium influx (Meyer-Franke et al. 1995; McAllister et al. 1996; Vaillant et al. 1999), raising the possibility that presynaptic corelease of a neurotransmitter and BDNF could have more dramatic effects on the postsynaptic neuron than the release of either of these stimuli alone. Such activity-dependent release of BDNF at central synapses could play an essential role both during development and in the adult. For example, during development, appropriate formation of ocular dominance columns is absolutely dependent on appropriate afferent activity (for review, see McAllister et al. 1999), and either application of exogenous BDNF (Cabelli et al. 1995) or disruption of endogenous BDNF (Cabelli et al. 1997) is sufficient to perturb this developmental process. Moreover, in the mature hippocampus, BDNF can modulate the strength of synaptic transmission at both the presynaptic and postsynaptic neuron (Kang and Schuman 1995, 1996; Levine et al. 1995, 1998; Gottschalk et al. 1998), and elimination of one BDNF allele in the BDNF+/− mice is sufficient to dampen long-term potentiation (LTP), an effect that can be rescued by the addition of exogenous BDNF (Korte et al. 1996; Patterson et al. 1996). On the basis of these considerations, we have hypothesized that BDNF may function, at least in part, by activity-dependent release from presynaptic terminals and subsequent activation of postsynaptic TrkB receptors. In this paper we have tested this hypothesis and demonstrate that elevated activity leads to rapid activation of synaptic TrkB receptors in the cortex and that pharmacological activation of brain-stem noradrenergic neurons, which synthesize and anterogradely traffic BDNF, is sufficient to cause rapid TrkB receptor activation on postsynaptic cortical neurons.