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Induction of Protein Deletion Through In Utero Electroporation to Define Deficits in Neuronal Migration in Transgenic Models
Published on: January 12, 2015
Defective neuronogenesis in the absence of Dlx5
Marzia Perera1, Giorgio R Merlo, Sara Verardo
1Laboratorio di Biologia dello Sviluppo, Istituto Nazionale per la Ricerca sul Cancro-IST, 16132 Genova, Italy.
Abstract:
Dlx genes play an important role in the control of the development of the central nervous system (CNS). Single or compound inactivation of Dlx1, Dlx2, or Dlx5 in the mouse causes defects of neuronal migration and differentiation. Dlx5, in particular, is essential for the correct development of the olfactory system. Targeted inactivation of Dlx1 and Dlx2 in the mouse results in abnormal neuronal differentiation in the embryonic subcortical forebrain and is associated to the loss of Dlx5 and Dlx6 expression. So far, however, it has been impossible to investigate the role of Dlx genes on late neurogenesis, as their inactivation leads to perinatal death. We have now generated cultures of neural stem cells (NSCs) derived from embryonic and newborn Dlx5-null mice, and we have compared their capacity to differentiate in vitro to that of equivalent cells derived from normal littermates. We show here that in the absence of Dlx5, NSCs derived from newborn animals have a severely reduced capacity to generate neurons. This is not the case for cells derived from E12.5 embryos. Forced expression of Dlx5 in cultures of newborn mutant NSCs fully restores their neuronogenic potential. Our data suggest that Dlx5 is essential for secondary (postnatal) neuronogenesis.
Insights
Distler, like homeobox (Dlx) genes are crucial for central nervous system (CNS) development. Dlx5 is essential for postnatal neurogenesis, as its absence in newborn neural stem cells severely impairs neuron generation.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Distler, like homeobox (Dlx) genes are critical regulators of central nervous system (CNS) development, influencing neuronal migration and differentiation.
- Previous studies indicate Dlx5 is vital for olfactory system development, but its role in late neurogenesis remained unexplored due to perinatal lethality of knockout models.
Purpose of the Study:
- To investigate the role of Dlx5 in late (postnatal) neurogenesis using in vitro neural stem cell (NSC) cultures.
- To determine if Dlx5 is required for the generation of neurons from postnatal NSCs.
Main Methods:
- Generation of NSC cultures from embryonic (E12.5) and newborn Dlx5-null mice and their wild-type littermates.
- In vitro differentiation assays to compare neurogenic potential between mutant and wild-type NSCs.
- Forced expression of Dlx5 in newborn Dlx5-null NSCs to assess rescue of neuronogenesis.
Main Results:
- NSCs from newborn Dlx5-null mice exhibited a significantly reduced capacity for neuronal differentiation compared to wild-type controls.
- NSCs from embryonic Dlx5-null mice (E12.5) showed no impairment in neurogenesis.
- Forced expression of Dlx5 in newborn mutant NSCs fully restored their neuronogenic potential.
Conclusions:
- Dlx5 is essential for secondary (postnatal) neurogenesis, regulating the generation of neurons after birth.
- The function of Dlx5 in neurogenesis is stage-dependent, being critical for postnatal development but not embryonic development.
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