Cbln1 Directs Axon Targeting by Corticospinal Neurons Specifically toward Thoraco-Lumbar Spinal Cord.

Corticospinal neurons (CSN) are centrally required for skilled voluntary movement, which necessitates that they establish precise subcerebral connectivity with the brainstem and spinal cord. However, molecular controls regulating specificity of this projection targeting remain largely unknown. We previously identified that developing CSN subpopulations exhibit striking axon targeting specificity in the spinal white matter. These CSN subpopulations with segmentally distinct spinal projections are also molecularly distinct; a subset of differentially expressed genes between these distinct CSN subpopulations regulate differential axon projection targeting. Rostrolateral CSN extend axons exclusively to bulbar-cervical segments (CSNBC-lat), while caudomedial CSN (CSNmedial) are more heterogeneous, with distinct, intermingled subpopulations extending axons to either bulbar-cervical or thoraco-lumbar segments. Here, we report, in male and female mice, that Cerebellin 1 (Cbln1) is expressed specifically by CSN in medial, but not lateral, sensorimotor cortex. Cbln1 shows highly dynamic temporal expression, with Cbln1 levels in CSN highest during the period of peak axon extension toward thoraco-lumbar segments. Using gain-of-function experiments, we identify that Cbln1 is sufficient to direct thoraco-lumbar axon extension by CSN. Misexpression of Cbln1 in CSNBC-lat either by in utero electroporation, or by postmitotic AAV-mediated gene delivery, redirects these axons past their normal bulbar-cervical targets toward thoracic segments. Further, Cbln1 overexpression in postmitotic CSNBC-lat increases the number of CSNmedial axons that extend past cervical segments into the thoracic cord. Collectively, these results identify that Cbln1 functions as a potent molecular control over thoraco-lumbar CSN axon extension, part of an integrated network of controls over segmentally-specific CSN axon projection targeting.SIGNIFICANCE STATEMENT Corticospinal neurons (CSN) exhibit remarkable diversity and precision of axonal projections to targets in the brainstem and distinct spinal segments; the molecular basis for this targeting diversity is largely unknown. CSN subpopulations projecting to distinct targets are also molecularly distinguishable. Distinct subpopulations degenerate in specific motor neuron diseases, further suggesting that intrinsic molecular differences might underlie differential vulnerability to disease. Here, we identify a novel molecular control, Cbln1, expressed by CSN extending axons to thoraco-lumbar spinal segments. Cbln1 is sufficient, but not required, for CSN axon extension toward distal spinal segments, and Cbln1 expression is controlled by recently identified, CSN-intrinsic regulators of axon extension. Our results identify that Cbln1, together with other regulators, coordinates segmentally precise CSN axon targeting.

Beam characteristics and stopping-power ratios of small radiosurgery photon beams.

Small megavoltage (MV) photon fields of dimensions less than 3 × 3 cm(2) are increasingly being used in modern radiation therapy. To our knowledge, small beam characteristics and dosimetric parameters, such as the energy spectra, particle fluence, and water-to-air stopping-power ratios (SPRs) directly affect the accuracy of small field dosimetry. This study presents the characteristics of small photon beams and investigates the variations of energy spectra of photons and electrons as a function of field size and their effects on the water-to-air SPRs for field sizes ranging from a small 4 mm diameter circular field to a 10 × 10 cm(2) field. It sheds light on the differences between small fields collimated by the cone accessory and X- and Y-jaws and on beam characteristics outside the primary radiation fields. In addition, we also investigated the use of an 'intermediate machine-specific-reference field' (Alfonso et al 2008 Med. Phys. 35 5179-86) to determine if the variations between a small and a reference field can be eased by introducing an intermediate 4 × 4 cm(2) field instead of a standard 10 × 10 cm(2) reference field. The Monte Carlo simulation codes BEAMnrc, DOSXYZnrc and SPRRZnrc were used in this study. The accelerator head and circular cone accessory were simulated in detail including two designs of flattening filters: one for a standard-dose rate (100-600 MU min(-1)) and the other for a high-dose rate (1000 MU min(-1)) 6 MV beam. The mean energy of photons at depths (1.5-30 cm) in water are 1.72-2.36 MeV, 1.55-1.97 MeV, and 1.44-1.74 MeV for field sizes of 4 mm diameter, 4 × 4 cm(2), and 10 × 10 cm(2), respectively. The mean energy also varies significantly for electrons at depths (1.5-30 cm): 0.99-1.25 MeV, 0.94-1.09 MeV, and 0.93-1.04 MeV for field sizes of 4 mm, 4 × 4 cm(2), and 10 × 10 cm(2), respectively. The calculated water-to-air SPRs at depths (1.5-30 cm) are 1.120-1.113, 1.121-1.117, and 1.122-1.119 for field sizes of 4 mm, 4 × 4 cm(2) and 10 × 10 cm(2), respectively. Although the differences in mean energy are > 20% for photons and > 5% for electrons between 4 mm field and 10 × 10 cm(2), the effects on the water-to-air SPRs are small (<0.5%). For detectors with responses to energy changes that are not negligible, significant energy variations between small fields and the reference 10 × 10 cm(2) field may have a significant impact on the dosimetry accuracy. However, the use of an intermediate field is capable of greatly reducing these energy variations. This study also found negligible differences in dosimetric parameters between beams with different flattening filters and different incident electron energies on the target when each has the same beam quality k(Q) values specified by %dd(10)(x).